Hindawi

Psychiatry Journal
Volume 2017, Article ID 5491812, 38 pages
https://doi.org/10.1155/2017/5491812

Review Article
Epigenetic and Neural Circuitry Landscape of
Psychotherapeutic Interventions

Christopher W. T. Miller
University of Maryland School of Medicine, 701 W. Pratt St., 4th Floor, Baltimore, MD 21201, USA

Correspondence should be addressed to Christopher W. T. Miller; chmiller@som.umaryland.edu

Received 10 December 2016; Accepted 11 April 2017; Published 25 May 2017

Academic Editor: Vaishnav Krishnan

Copyright © 2017 Christopher W. T. Miller. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

The science behind psychotherapy has garnered considerable interest, as objective measures are being developed to map the patient’s
subjective change over the course of treatment. Prenatal and early life influences have a lasting impact on how genes are expressed
and the manner in which neural circuits are consolidated. Transgenerationally transmitted epigenetic markers as well as templates
of enhanced thought flexibility versus evasion can be passed down from parent to child. This influences gene expression/repression
(impacting neuroplasticity) and kindling of neurocircuitry which can perpetuate maladaptive cognitive processing seen in a number
of psychiatric conditions. Importantly, genetic factors and the compounding effects of early life adversity do not inexorably lead
to certain fated outcomes. The concepts of vulnerability and resilience are becoming more integrated into the framework of
“differential susceptibility,” speaking to how corrective environmental factors may promote epigenetic change and reconfigure
neural templates, allowing for symptomatic improvement. Psychotherapy is one such factor, and this review will focus on our
current knowledge of its epigenetic and neurocircuitry impact.

1. Introduction equivalence [1, 2], has garnered considerable controversy [3],

The effects of psychotherapy from a clinical perspective are
growing in evidence base, particularly given the desire within
the scientific community to translate concepts which many
times are subjective and abstract into demonstrable and
replicable effects. This has gained substantial ground recently,
as the benefits of psychotherapy have been demonstrated on
multiple levels, including its epigenetic, neurocircuitry, and
neuroendocrine influences. Also, animal models have shown
the benefits of continued environmental enrichment (EE)
on psychopathological phenotypes, which carries exciting
translational value, particularly given that some of these
studies utilize animals which are genetically bred to exhibit
maladaptive phenotypes. Thus, the environment can con-
tinue to influence behavioral paradigms throughout the life
cycle. The premise of most forms of psychotherapy highlights
the importance of the therapeutic alliance and the devel-
opment of a rapport that feels containing for the patient.
Indeed, the “Dodo Bird Verdict,” positing that in the end all
forms of psychotherapy have some degree of empirical
but on a neuroscientific level there may be some value to it,
given that much of what has been shown as the effects of
continued psychotherapeutic action has been activation of
more interpersonally attuned areas of the brain, as well as
greater expression of genes allowing for plasticity in areas
involved with higher cognitive processing and with fine-
tuning the activity of subcortical areas. Neuroendocrine and
neurocircuitry templates established early in life will be the
default manner of negotiating environmental stimuli, and
conditioned responses, especially as they pertain to interper-
sonal models of interacting, will arise within the therapeutic
dyad (i.e., the therapist and patient). Assessing the patient’s
symptomatology and personality structure in light of early
life experience has been enriched by research investigating
how their individual make-up came to be, and reshaping of
endocrine responses and select activation of certain neural
networks, in particular when faced with life stressors, is a
powerful indicator of therapeutic response. This paper will
aim to outline how early life experience lays down this
template, which in many ways is enduring and very difficult to
2 Psychiatry Journal
undo, and how the environment factors can foster significant
change throughout one’s life.
2. Prenatal and Early Life Influence
Most central nervous system (CNS) neurogenesis occurs over
a period spanning just over two years, and most telencephalic
neurons are generated before birth [4]. Contingent and
appropriate responses from the infant’s primary caregiver
are crucial in facilitating CNS development, and the more
interpersonally attuned right hemisphere shows a more accel-
erated growth during the late fetal and early postnatal periods
[5, 6]. Attunement to the child also informs how he or she will
internalize the model for social interactions; early life neglect
and abuse can lead to a plethora of psychiatric and somatic
conditions, including growth delays, immune dysregulation,
low levels of oxytocin, and impairment in social reciprocity
[7–10]. Thus, the “psychobiologically attuned caregiver” has a
pivotal role in regulating an infant’s brain development [11]. In
ideal situations, the caregiver will be attuned to the child and
able to provide comfort during distressing states, something
which will allow for the child to emerge with a basic sense of
safety and trust, in particular as motor skills are furthered and
exploration of the world is the next task to face, something
which may be exciting or terrifying.
2.1. Genetic Considerations
2.1.1. Vulnerability Genes. Genetic vulnerability is a topic
of some controversy, particularly as we learn more about
the complex interaction between an individual’s genetic
endowment and how the environment influences expression.
A number of genes which have been termed “vulnerability
genes” have been identified and replicated in human studies
as conferring a particular risk of psychopathology. The
counterpoint to this will be presented later in the paper,
underlining concept of “differential susceptibility” [12, 13], a
hypothesis which posits that there is varying susceptibility of
individuals to the effects of the environment depending on
genetic make-up. As such, some individuals would display
worse outcomes in negative environments but flourish more
in positive environments, highlighting the “plastic” nature
of their responses [14]. The genes that will be discussed in
this paper are primarily those upon which psychotherapy
has been shown to have an impact. Caspi et al. outlined
two particular genes in groundbreaking studies which high-
lighted one’s susceptibility to behavioral and emotional dys-
regulation, when coupled with an adverse early environment
[15, 16]. The first of the studies was performed in human
subjects of both genders (with a sample of roughly 1,000
individuals), following them across multiple time points
throughout their lives, and demonstrated that a low-
functioning allele of monoamine oxidase A (MAO-A) was
associated with numerous adverse outcomes later in life,
relating particularly to conduct disorder, antisocial person-
ality disorder, violence, and incarceration [15]. As MAO-A is
responsible for the breakdown of serotonin, norepinephrine,
and dopamine, suboptimal functioning can lead to an excess
in neurotransmitter availability. An excess of serotonin can be
associated with amygdala hyperreactivity and altered threat
processing [17]. Also, elevated levels of norepinephrine and
dopamine have been associated with greater externalizing
behaviors and aggressiveness [18], more pronounced when
immersed in a threatening and unpredictable environment.
Importantly, MAO-A is an X-linked gene, and males carrying
a hypoactive allele may have in effect a knockout gene.
Another vulnerability gene is the Solute Carrier Family
6, member 4 (SLC6A4), which codes for the serotonin trans-
porter (5-HTT or SERT). The short (s) allele of the serotonin
transporter-linked polymorphic region (5-HTTLPR) has
been associated with later development of psychopathology
(in interaction with an adverse environment), in particular
major depressive disorder (MDD), suicide attempts, anxiety
disorders, and attention-deficit and hyperactivity disorder
(ADHD) [16, 19, 20]. From early on, maternal sensitivity may
allay some of the negative emotionality in children showing
the s allele, demonstrating the interplay with the environment
[21]. The s allele (coding for a hypofunctional serotonin trans-
porter) would impair reuptake of serotonin into the presy-
naptic terminal, increasing availability of this neurotransmit-
ter in the synaptic cleft. In addition to the effect on amygdala
reactivity highlighted above, it is noteworthy that the seroton-
ergic system is closely linked with functionality of inhibitory
GABAergic systems (particularly with regard to prefrontal
cortex-basolateral amygdala connectivity, mediated through
GABAergic intercalated cells), additionally informing how
fear modulation and threat processing will take place during
life [22]. Animal models of knockout groups for the SERT (in
an attempt to replicate the effects of the s allele) have shown
that the amygdala is primed for aversive conditioning, given
the decrease in 5-HT1A sensitivity [23] and an increase in
5-HT2C expression [24], serotonin receptor subtypes which
are anxiolytic and anxiogenic, respectively. It is important
to underscore that these are far from negligible genetic
vulnerability markers; for instance, the prevalence in the
general population of the s allele of SERT is around 43% [19]
and that of a hypofunctioning MAO-A allele is approximately
29% [25].
High-induction single nucleotide polymorphisms (SNPs)
of the FK506 binding protein 5 (FKBP5) gene (see discussion
below in Section 2.1.2) have been associated with higher glu-
cocorticoid receptor (GR) resistance and hence greater circu-
lating cortisol levels secondary to a reduced negative feedback
loop. Given higher baseline cortisol, an individual may have
more difficulty recovering from a psychosocial stressor, as
well as more enduring symptoms during this recovery period
[26]. Studies have associated these SNPs with a higher
prevalence of MDD [27] and suicide attempts [28], both in
interaction with environmental adversity. The brain-derived
neurotrophic factor (BDNF) Val(66)Met carriers also show
an environmentally informed change in circulating BDNF
levels, with lower concentrations being found in individuals
who have suffered childhood abuse [29].
The following section will discuss epigenetic modifica-
tions which can occur with adverse environmental exposure;
synergistic effects of genetic along with epigenetic changes
may lead to subsequent psychopathology, as will be explored
further.
Psychiatry Journal
2.1.2. Epigenetic Changes. An exhaustive review of epigenetic
changes associated with early life adversity is beyond the
scope of this paper. There are comprehensive reviews which
can detail DNA and histone changes and nontranscribing
RNAs, as well as their effects on psychopathology, in much
greater detail [30, 31]. Given its focus in recent psychotherapy
research, DNA methylation will be the primary point of dis-
cussion with regard to epigenetics. Gene methylation serves a
repressive function, as it leads to a tighter coiling of the chro-
matin, decreasing expression by blocking access of transcrip-
tion proteins to the specific sequences. Methylation primarily
occurs on cytosine nucleotides, forming methyl-cytosine.
Despite a genome-wide wave of demethylation which takes
place after fertilization, a number of methyl groups still
remain in the DNA by action of the methyl maintenance
transferases. This allows for inheritance of epigenetic changes
from parent to offspring [32], a phenomenon which can
be correlated with subsequent behavioral patterns and psy-
chopathology. Methylation per se is necessary for maintain-
ing neuronal structural integrity; methylation enzyme knock-
out has been shown in animal models to cause profound
intellectual disability [33]; experimental models in human
embryonic stem cells show that deletion of DNA methyltrans-
ferase 1 (DNMT1) resulted in rapid cell death due to DNA
damage and G1 cell cycle arrest, being thus incompatible with
life [34]. In addition to its regulatory function, gene methy-
lation can also be an epigenetic marker of trauma [35] and
may affect a wide range of neuroendocrine and neurotrans-
mitter systems, as well as informing later psychopathology.
How transgenerational methylation impacts offspring is the
subject of much current research effort. It has been displayed
in animal models regarding fears of certain odors [36]; in
the cited study, aversive conditioning to acetophenone was
induced in F0 mice. Offspring of these mice demonstrated
enhanced sensitivity to this odor, as indicated by an odor-
potentiated startle response. There was a significant increase
in populations of olfactory sensory neurons which detect
this odor, as well as hypomethylation of the gene (Olfr151)
responsible for transcribing the particular acetophenone-
sensitive receptor (M71), with increased genetic and receptor
expression. Another study showed that male mice exposed to
unpredictable maternal separation early on later developed
anxiety and depressive-like behaviors, as well as impairment
in social functioning; these phenotypes were later observed
in their offspring, even in circumstances of adequate mater-
nal care [37, 38]. While human infants exposed to severe
neglect have shown widespread patterns of hypermethylation
detected in blood cells [39], a number of key genes involved in
the regulation of the stress response and of neurogenesis can
be affected by early life adversity. The following discussion
will highlight some of these genes and the implications of
their epigenetic modifications.
FKBP5 is a cochaperone which, along with heat shock
proteins, facilitates transportation of cortisol to the nucleus,
where it exerts effects on gene transcription. The function
of FKBP5 is to increase the resistance of the GR to cortisol,
in effect increasing levels of the latter. An excessive amount
of cortisol may have a cytotoxic effect, triggering the apop-
totic cascade [40]. Indeed, epigenetic methylation of the
3
GRs (including those located in the hippocampus) and
demethylation of the FKBP5 gene have been implicated in
the response to stress [41], and these can lead to persistently
elevated cortisol levels. Maternal stress during pregnancy
can induce placental gene methylation of FKBP5 and of 11-
beta-hydroxysteroid dehydrogenase 2 (the latter involved in
inactivating glucocorticoids) [42]; this has an adverse impact
on fetal coupling, a correlation between the fetus’s heart
rate and motor activity and an indicator of nervous system
development. What seems to be the evolutionarily “adaptive”
message from the parent to the child is that the world is a place
that needs to be considered dangerous, and as such the child’s
neuroendocrine system is primed to react to its environment
in such a way. In a study of Holocaust survivors [43],
FKBP5 was shown to be hypermethylated in survivors and
demethylated in their offspring. Trauma disorders can be
associated with low cortisol levels, which would in theory
allow for norepinephrine to be released excessively without
the opposing effects of the glucocorticoid, accounting for the
characteristic symptom spectrum, with heightened alertness
and intrusive reexperiencing [44]. However, what is passed
down to the infant is an epigenetic modification which would
allow for increased cortisol from early on, again emphasizing
that the child should be prepared for trauma and, seemingly
reinforcing the self-kindling cycle, parental trauma has been
associated with subsequent trauma in their offspring [45].
Methylation of genes impacting neurotransmitter sys-
tems has also been described. In a rat model, early life
adversity can lead to methylation of the glutamic acid decar-
boxylase 1 promoter (GAD1) [46]; this enzyme is responsible
for conversion of glutamate to gamma-amino butyric acid
(GABA); thus, gene repression would lead to a relative excess
of glutamate relative to GABA; glutamate serves a vital role
in the normal development of synapses, and excess levels
can lead to elimination of nonredundant circuits, particularly
during the perinatal period. In addition, there may be
methylation of genes which underlie expression of N-methyl
D-aspartate (NMDA) receptor subtypes [47]; NMDA subunit
switch is fundamental for consolidation of synapses and thus
of long-term memory [48], and this may be impaired in
the event of adverse experiences. Furthering this argument,
the BDNF gene has also been shown to suffer epigenetic
changes in response to childhood adversity. Given the affinity
of methyl groups for cytosine, it is of particular interest that
the BDNF gene is rich in cytosine-guanine (CG) islands, and
methylation of this gene can persist into adulthood [49]. This
can influence neurogenesis throughout the life cycle, as well
as showing an association with later pathology; BDNF gene
methylation has been associated with completed suicides
[50] as well as with development of borderline personality
disorder (BPD) [51].
Further discussion of the mother-child dyad will be pre-
sented later, in particular as it relates to neural circuitry for-
mation and strengthening of particular networks depending
on the level of attunement. Oxytocin is a neuropeptide which
is involved with social affiliation, maternal behavior and trust,
bonding, and ascribing salience to social cues [52]. Early life
stress may lead to low levels of oxytocin in the cerebrospinal
fluid (CSF) of women [53], thus potentially impairing the
4 Psychiatry Journal
bonding process with her infant; rodent models have also
demonstrated a decrease in oxytocin receptors (OXTR) in the
brain when exposed to conditions of suboptimal nurturing
[54]. Despite low levels of oxytocin and of OXTR gene
expression having been linked with adverse outcomes (e.g.,
autistic traits and elements of psychopathy) [55, 56], they
are not unidirectionally and inextricably associated with
psychopathology [57, 58], and the mediating effect of the
environment has been demonstrated in recent studies. Dif-
ferential susceptibility may factor into this mediating effect,
as higher expression of OXTRs may increase an individ-
ual’s capacity for empathy [59] but may also predispose to
greater sensitivity to negative environmental effects, with, for
instance, higher risk for separation anxiety and disorganized
attachment [60, 61]; excessive levels of oxytocin may also
cause greater stress sensitivity, as there is an association with
higher risk of anxiety disorders [57]. SNPs within the OXTR
gene do not necessarily lead to adverse outcomes on their own
and indeed may be adaptive when dealing with adverse
situations (e.g., the SNP rs53576, a guanine to adenine sub-
stitution, may confer resilience in G/A and A/A individuals
in the development of psychopathology when faced with
stressful circumstances, as compared to G/G individuals)
[62]. However, there are several SNPs (and associated CpG
site methylation patterns) which can interact with abuse to
increase the occurrence of anxiety and depressive symptoms
(though significance is variable) [58, 61, 63]. These associ-
ations are clearly complex, and optimal levels of oxytocin
are instrumental in mitigating amygdala and brainstem
hyperactivity in the fear response [64]. Thus, genetic and
epigenetic factors impacting its effects are of importance
when considering subcortical circuitry activation in a child’s
development, as it is informed by the early environment and
factors into later psychopathology.
2.2. Neural Circuitry Formation. Cortisol is produced in
the zona fasciculata of the adrenal and is released as
part of the adaptation to stressful circumstances, working
in tandem with norepinephrine to allow for an adaptive
response to a given situation. Secretion is regulated by the
hypothalamus-pituitary-adrenal (HPA) axis, and circulat-
ing cortisol provides negative feedback to block proximal
release of corticotropin-releasing hormone (CRH) from the
hypothalamus. While the amygdala has been shown to
become active very early on in life [65, 66] and conditioned
positive and negative responses to stimuli occur from an
early age, activation is contingent on the presence of cortisol
(the amygdala is rich in GRs) [67]. Indeed, during the stress
response, there is a reciprocal loop between the HPA axis
and amygdala, as the latter stimulates release of CRH and
can further increase cortisol levels [44]. However, prior to the
amygdala becoming activated, there is a period during which
the presence of the mother effectively “turns off” the GRs
in the amygdala, thus blocking its activation by circulating
cortisol, something which has been shown in rat pups [68]
and which has applicability to humans as well. This is termed
the stress “hyporesponsive” or “nonresponsive” period (here
abbreviated as SHP). During the human infant’s develop-
ment, this corresponds roughly to the first 12 months of life
[69]. This is a crucial period for attachment, and premature
activation of the amygdala during this time can occur with
early life stress and subsequent stimulation of the HPA axis
and secretion of cortisol, as GRs can become activated when
they should adaptively be blocked. Importantly, the effects
of this premature activation can have long-lasting effects
on the neuroendocrine response [70]. Thus, in the event
of an abusive caregiver, even though non-amygdala-related
attachment circuitry (much of which involves olfactory
circuits and noradrenergic pathways) would draw the child
closer to the caregiver, the early conditioning of the amygdala
due to premature plasticity owing to elevated cortisol levels
may label this caregiver as dangerous. This creates the
confusing picture of attaching to destructive caregivers in a
disorganized/approach-avoidance manner, a template which
can become activated later in life and reenacted in adult rela-
tionships. The SHP has an interesting correlation with Erik
Erikson’s first stage of development, “Trust versus Mistrust”
[71], lasting from zero to 12 months of age, and lining up
with the child’s greater acquisition of motor skills as well as
the time around which the maternal “blockade” of GRs is
normally lessened. At this time, conditioned responses to the
environment will come more to the fore (as the amygdala is
allowed to become plastic through its response to cortisol),
with the child’s preceding experience greatly influencing
whether the template of the world to be discovered will be
imbued with a predominantly positive or negative valence. It
is of note that, through influence of the basolateral amygdala
(BLA), memories that are high in emotional content will be
encoded in a more efficient manner than emotionally neutral
experiences [72], adding to the significance of how one’s early
affective responses are consolidated.
As a manner of providing contextual and spatial data
to an individual’s experiences, the hippocampus (associated
primarily with episodic memory and contributing to exec-
utive functioning) can aid in decreasing activation of the
amygdala [73], countering (based on experience) the primar-
ily salience-based amygdala response. The amygdala, partic-
ularly in cases of hyperactivation when faced with stimuli
which are sensed to be dangerous, can inhibit the hippocam-
pus as well, blocking access to contextual memories which
could allay fear-based responses. This is relevant, for instance,
in posttraumatic stress disorder (PTSD), as the reexperienc-
ing component heightens one’s reactivity, creating an inflex-
ible and conditioned reaction to situations removed from
the original traumatic event [74], with impaired access to
hippocampal contextual input which could allow for a more
informed and less reactive response. From an early devel-
opmental perspective, this becomes highly relevant given
the infantile amnesia phenomenon, which has posited that
early memories (prior to around age four years) [75] will be
erased by subsequent ones within the hippocampal circuitry
(though it has been recently suggested that there may be
mnemonic traces which could be subsequently activated)
[76]. Given the earlier and later consolidation of amygdala
and hippocampal nuclei, respectively, an individual can
Psychiatry Journal
attribute strongly positive or negative salience to environ-
mental components but not have access to hippocampal
function as a manner of creating some “perspective” on
the situation. This may be internalized as a template and
default response to situations which may be very difficult to
modify based on later experience, particularly if subsequent
environmental factors are adverse as opposed to nurturing.
Certain conditions (e.g., BPD, anxiety disorders, and MDD)
which show preferential activation of the amygdala over the
hippocampus may be characterized by all-or-none thinking,
indicating a more crystallized conditioned response. The
neural correlates of these conditions will be expanded upon
later. Importantly, even when information is being integrated
into the hippocampus, it may be distorted by the emotionally
driven response informed by the amygdala, leading to faulty
processing during information compression from the dentate
gyrus to layer CA3 [77], both areas which have shown
decreased volume in childhood abuse [78].
BDNF is pivotal in promoting hippocampal neuronal
survival and plasticity [79]; activation of this growth factor
throughout the lifespan has been linked with postmitotic
neurogenesis within the hippocampal dentate gyrus. There
is a close correlation between levels of glucocorticoids and
BDNF, a balance which is necessary to allow for consolidation
of learning [80]. However, excessive levels of glucocorticoids
will lead to synaptic loss and suppress the release of BDNF,
decreasing plasticity in several brain regions including the
hippocampus, as the latter is rich in GRs. The importance of
this lies in the negative feedback the hippocampus provides to
the HPA axis, blocking release of CRH and curtailing further
release of cortisol downstream. For this to happen in a bal-
anced manner, the hippocampus needs to express sufficient
GRs for this feedback loop to occur. Illuminating studies have
shown that early life adversity can lead to a paucity of GRs on
the hippocampus, thus hindering the feedback mechanism
and leading to elevated levels of cortisol. Rodent models have
shown that mothers that provide less licking and grooming
(LG) to their pups will result in the latter having reduced
hippocampal GR RNA (with fewer expressed receptors),
elevated levels of cortisol (due to impaired negative feed-
back), decreased BDNF levels, and consequent reductions
in hippocampal plasticity, as excess cortisol is neurotoxic,
as mentioned [49, 81–84]. Thus, the destructive loop per-
petuates itself, as the hippocampal neurogenesis is impaired
due to high circulating cortisol, and the HPA axis is further
kindled by a lack of feedback. Early life adversity has also been
associated with an increase in BDNF in the BLA, promoting
conditioned changes which may be more resistant to mod-
ification later in life [85]. As such, BDNF can have circuit-
specific effects depending on the area involved, dampening or
consolidating negative effects of stress (the reader is referred
to Section 3.1. for a discussion of the prodepressant effects
of BDNF release from the ventral tegmental area (VTA) to
the nucleus accumbens (NAc) in chronic stress paradigms).
Thus, there can be a predominance of affective or contextually
driven default responses to given situations, depending on
the amygdala/hippocampus balance, and the memory and
affective salience are internalized in association with individ-
uals and circumstances, generating conditioned templates,
5
dictating how one will negotiate future experiences. There
is also a functional coupling between the amygdala and the
orbitofrontal cortex (OFC) [86], an area of the brain associ-
ated with reward and punishment considerations regarding a
particular setting; thus, the affective salience informed by the
amygdala is paramount in the approach-avoidance paradigm
underlying behavioral output. This amygdala-OFC connec-
tion will create associations of neutral objects with natural
reinforcing or punitive salience [87]. Much of the circuitry
discussed will underlie immediate situational responses and
may result in impulsivity and limited flexibility to deal with
novel or complex scenarios.
Subcortical circuitry will connect with higher corti-
cal areas and, depending on the hippocampus-amygdala-
hypothalamus output, more “cognitive” or “affective” areas
may be preferentially activated as a form of adapting to the
subcortical feedback (Figure 1). The prefrontal cortex (PFC)
will function to negotiate more complex social behaviors
through connections with the default brain circuitry; this
may be done in more or less flexible manners, depending on
which cortical pathways are activated. The anterior cingulate
cortex (ACC) is an important intermediary in bridging areas
involved in emotional processing with those involved in
more nuanced cognitive functions. It will monitor error and
conflict, as well as assessing the motivational and emotional
relevance of stimuli, and thus predict the potential value of
rewarding or punishing situations and being able to weigh
different courses of action as informed by this input [88]. As
alluded to above, there are two main cortical subdivisions
which can be preferentially activated depending on feedback
from the ACC. The ventral (“affective”) subdivision regulates
autonomic/visceral responses to stress, as well as contributing
to the valence one assigns to a particular stimulus. This
subdivision is composed of the rostral ACC (rACC), sub-
genual ACC (sgACC), and ventromedial prefrontal cortex
(vmPFC). The anterior portions of the ACC have connections
with subcortical areas associated with instrumental responses
to situations, such as the amygdala, brainstem nuclei, and
periaqueductal gray (PAG); there are also connections with
brain areas involved with reward and risk considerations,
such as the NAc and the OFC [89]. These portions of the
PFC and cingulate cortex are key in the top-down control
of limbic activation and thus emotional control. Both the
ACC and vmPFC have connections with the amygdala and
are activated during the process of fear extinction [90–92];
due to this connection, the vmPFC can allow for a more
informed cognitive appraisal of stimuli and aid in controlling
the subsequent activation of the amygdala. In particular, the
connection between the vmPFC and the OFC will help in this
process of guiding behavior in the context of emotional input
and coding one’s emotional and motivational values [93, 94],
which will integrate on a more conscious level the approach-
avoidance templates discussed previously. Importantly, areas
of the affective subdivision are also involved with empathic
attunement and theory of mind (along with other areas
such as the temporoparietal junction and the superior tem-
poral sulcus) [95–97]. This will factor into later discussion
regarding the effects of psychotherapy and the fundamentally
interpersonal nature of therapeutic action.
6 Psychiatry Journal

Sensory stimuli
Downstream release of cortisol
and monoamines

Information regarding
stimuli valence Amygdala activation: attribution
of positive or negative salience to 4 5
stimuli

2
Hypothalamus: input to
Orbitofrontal cortex: risk and Reciprocal inhibitory pituitary/adrenal axis and
3 input
reward considerations activation of brainstem nuclei
based on threat estimation

Information regarding Hippocampal activation:

episodic experience contextual data input 4
with stimuli

(a)

FC FC
dlP dlP
dor Cingulate dor Cingulate
ros ros
V Vm
PFmC sg PFC sg
OFC HC OFC HC

Am Am

(b)

Figure 1: Depiction of the subcortical-cortical communication which will inform whether the dlPFC or vmPFC will be preferentially activated
in response to environmental stimuli. (a) shows how, as the individual perceives an element in the environment (the thalamus is not portrayed
in this figure), the amygdala will be activated, and positively or negatively valenced associations will emerge based on past experience. The
hippocampus will provide some level of contextual data based on episodic memory, and the OFC will weigh risk and reward considerations
based on input from these two structures. Subsequent neuroendocrine responses will ensue, with the hypothalamus being more or less driven
to initiate downstream cortisol release, as well as stimulating brainstem nuclei for release of monoamines, depending on the subjective sense
of danger felt to be present. (b) illustrates the subsequent higher cortical level activation that will occur after this initial communication. The
subcortical-cortical connection will be mediated by the ACC (either ventral or dorsal portions), which will divert activation preferentially
towards the dl or vmPFC. Left panel: in instances of lower perceived environmental threat, the vmPFC is activated via portions of the sgACC
and the rACC; there is greater inhibitory connection with the amygdala, thus allowing for greater top-bottom mitigation of the fear response
(also aided by the inhibitory contextual hippocampal input); more robust development of the vmPFC-amygdala and hippocampus-amygdala
control mechanisms can allow for more controlled responses to the environment, even when there may be potential threat, as cognitive
control and contextual data will prevent excessive reactivity and stimulus generalization, permitting greater flexibility and hence more
adaptive responses. The vmPFC has been shown to be hypoactive in cases of child abuse, major depressive disorder, borderline and antisocial
personality disorders, and posttraumatic stress disorder, among others (refer to text for more detail). Right panel: in situations of amygdala-
driven bottom-top communication, as is seen in anxiety disorders, posttraumatic stress disorder, and borderline personality disorder, portions
of the sgACC and the dACC may be preferentially activated and access the dlPFC, resulting in excessive cognitive control, attempts to suppress
distressing memories, and lack of attunement with one’s own emotional response, given the lack of inhibitory feedback onto the amygdala;
in (b), solid lines represent excitatory connections and dashed lines, inhibitory connections. dlPFC = dorsolateral prefrontal cortex; vmPFC
= ventromedial prefrontal cortex; OFC = orbitofrontal cortex; Am = amygdala; HC = hippocampus; Hy = hypothalamus; sg = subgenual
anterior cingulate cortex; ros = rostral anterior cingulate cortex; dACC = dorsal anterior cingulate cortex. The sgACC has connections to
both the vmPFC and the dlPFC, the implications of which are described in the text. This depiction is of the medial surface of the brain; the
dlPFC and portions of the OFC are located on the superolateral surface of the cerebrum, and their representations here are schematic.
Psychiatry Journal
The dorsal (“cognitive”) subdivision will include the
dorsal ACC (dACC), the hippocampus, the supplementary
motor area (SMA), the parietal cortex, and the dorsolateral
PFC (dlPFC). As will be discussed, the sgACC also factors
into the dorsal subdivision, which is germane in certain psy-
chiatric disorders. While the dlPFC is involved in executive
functioning, temporal information processing, the overcom-
ing of cognitive interference, and task switching, it may also
be involved in emotional avoidance and in the suppression
of unwanted memories and in avoidant behaviors towards
others [98]. Faulty activation may also lead to attributing
excessive salience to particular thoughts and stimuli/objects,
leading to perseverative and ruminative thinking and a
difficulty in negotiating novelty. Thus, potentially emotional
stimuli (including interactions with others) may be handled
through strategies which deploy excessive cognitive control
[99], as opposed to the greater cortical-subcortical connectiv-
ity described with the ventral subdivision, leading to a lack of
attunement with others and indeed with one’s own emotional
response. The dACC has a role in pain perception, response
selection, emotional regulation, and the fear response. It has
been implicated in a sense of social exclusion [100] and
has also been associated with child abuse and PTSD [101].
In effect, there seems to be an inverse correlation between
vmPFC and dACC activity [102]. Preferential activation of
the dACC can facilitate expression of the fear response, as
it directly projects onto the BLA, which in turn activates
the central amygdala (CeA), leading to brainstem nuclei
stimulation and an autonomic response. Importantly, the
vmPFC is bypassed in this process; the latter has a role
in decreasing amygdala hyperactivity by projecting onto
GABAergic intercalated cells (ITC) in the amygdala, which
will inhibit the CeA and dampen the autonomic response
[102]. With increased activity of the dACC, the ability of
an individual to empathize with others may be compro-
mised, and juvenile offenders with callous-unemotional traits
exhibit enhanced connectivity between the dACC and the
amygdala [103]. The dACC is a pivotal area in the social
feedback network, integrating the dorsal and medial PFC
[104]; thus, the valence of particular interpersonal input may
be more strongly negative depending on the dACC activity
level. Of note, it has been suggested that this brain area would
need to be activated in order to promote psychotherapeutic
change, particularly in modalities which would necessitate
attunement and mentalization strategies [105]. One can speak
of a “lateral bias” in circuitry activation when the dorsal
subdivision is predominantly activated, something which is
observed in multiple psychiatric disorders [106–110], as will
be discussed in detail later. Many of the conditions in question
have symptom spectra in which faulty emotional processing
and preferential (and many times maladaptive) activation
of cortical pathways occur which inform consolidated and
ruminative negative views of oneself and/or their environ-
ment. This circuitry illustrates the powerful influence that the
limbic structures can have on an individual’s default appraisal
and behavioral responses and may perpetuate the template
that certain situations cannot be thought about and processed
appropriately.
7
2.2.1. Implications for Early Life Adversity. As mentioned,
the right hemisphere is instrumental in the emotional
attunement between individuals, involved, for instance, in
detecting facial cues in others [111]. The mother-child dyad,
on a neurocircuitry level, activates multiple circuits involving
positive/negative valence, empathic attunement, and reward.
When a mother looks at her child, areas activated include
the amygdala, OFC, and fusiform gyrus; the latter two areas
have been described as forming the “neural signature” of the
parental response to the child’s face, being activated on the
order of milliseconds (implicating that there is a reward/risk
consideration that immediately happens when a mother
interacts with her child) [112–114]. The attuned mother will
interact in a manner which is experienced as rewarding for
her and soothing for the child; indeed, appropriate release
of oxytocin enhances maternal neural plasticity [115, 116].
The rewarding nature of this interaction is illustrated by
mesolimbic dopamine release [117] and activation of the NAc
[118]. Cortically, the mother’s ability to attune to her child is
dependent on activation of the mPFC which, as discussed, is
involved in the mentalization circuitry; this area is activated
when the child is showing signs of distress, indicating the
mother’s ability to understand its suffering and provide
comfort [119]. Thus, the mPFC is key in an individual’s ability
to access his or her own emotional response in a measured
manner, as well as allowing for access and understanding
of the emotional states of others. Lack of ability to do this
adequately can lead to feeling overwhelmed by affectively
charged situations, requiring cognitive evasion strategies.
This has relevance in the development and consolidation of a
child’s attachment schema, which begin to take shape within
the first year of life. A misattuned mother may not be able to
empathically connect with her child, limiting her abilities to
be soothing in moments of distress, and contributing to the
child’s perception that such moments may not be amenable
to finding comfort in another person. Misattunement in
itself predicts subsequent disorganized attachment in the
child [120], speaking to this internalization and “organizing”
schema of how interpersonal relationships are negotiated
moving forward. This can be noted when the mother looks
at her child and shows signs of shame, fear, disgust, or disso-
ciative phenomena, among others; this can have a profound
impact on the child initially on a sensorimotor, autonomic,
and affective level and eventually take on greater cognitive
dimensions [121, 122]. Attachment schema have been shown
to be transmitted transgenerationally [123, 124], and the
maternal neurocircuitry template deployed in interpersonal
interactions can be passed down also. The establishment of
such patterns of attachment early on is particularly relevant
given that early internalized representations have been shown
to correlate with relational patterns displayed as an adult
[125]. Speaking more specifically to the neural circuitry acti-
vated in mothers who themselves show insecure attachment
and are faced with their distressed child, what is noted is
predominant activation of the dorsal subdivision, in partic-
ular the dlPFC, suggesting attempts to use cognitive control
strategies to handle the situation [126]. She will also show
decreased activation in the ventral striatum (where the NAc is
located), indicating a lack of a hedonic response, and
8 Psychiatry Journal

Abused child
Insecure mother

FC FC
dlP dlP

pSTS
BG BG
vmP vmP
FC FC
OFC FG OFC
AI AI

Am Am

Preferential activation Preferential activation

Hypoactive area Hypoactive area
(a) (b)

Figure 2: Demonstration of the transgenerational transmission of a neurocircuitry template of misattunement. (a) demonstrates the pattern
observed in the insecure/misattuned mother. When looking at her child, a mother will quickly access a complex interconnected network,
including facial identification areas (FG) and empathic attunement areas (vmPFC and pSTS). Importantly, in addition to these areas,
there is connection with areas of the brain which are involved with immediately valenced reactions (amygdala), reward-risk considerations
(OFC), and feelings of empathy versus disgust and shame (insula). Thus, there is a prominent subcortical input which will inform whether
approaching one’s child is something considered desirable or potentially dangerous. The misattuned mother will preferentially activate
cognitive control areas (dlPFC) as opposed to the more empathically attuned vmPFC; in addition, there is heightened activation of the anterior
insula (associated with social pain and unfairness) and lessened activation of areas of the VS (associated with reward to external stimuli). Thus,
the model for avoidance of emotional attachment is engendered, and there is a corollary in this mother’s child, which is illustrated by the CNS
findings in the abused child. (b) illustrates the findings seen in a child who has suffered abuse, which seem to mirror in some important ways
what was seen in the mother. Hyperactivity of the amygdala and decreased volume of the hippocampus can result in highly affectively driven
responses to stimuli without access to contextual data which would allow for a less polarized reaction; thus, the greater input of the amygdala
will drive the OFC balance and favor the dlPFC with regard to how the environment is negotiated; hypoactivation of the vmPFC will impair
one’s ability to control this amygdala response and promote fear extinction. Also, the child shows a diminished ability to see the potential
positive value of rewarding stimuli due to hypoactivation of the corpus striatum, impacting how interpersonal interactions are seen, and
creating a model of mistrust and negativity when dealing with other people. FG = fusiform gyrus; vmPFC = ventromedial prefrontal cortex;
pSTS = posterior superior temporal sulcus; OFC = orbitofrontal cortex; dlPFC = dorsolateral prefrontal cortex; BG = basal ganglia; Am =
amygdala; AI = anterior insula; HC = hippocampus. As shown in the figure, green arrows indicate greater or preferential activation, whereas
orange arrows indicate the opposite. As mentioned in Figure 1, this depiction is of the medial surface of the brain; the dlPFC, portions of
the OFC, pSTS, AI, and FG are located on areas of the superolateral and inferior surfaces of the cerebrum, and their representations here are
schematic.

heightened activation of the anterior insula. The insula is a
complex cortical area which is involved with anticipating and
experiencing negative outcomes [106], as well as being inte-
grated into the empathic response network; its interoceptive
integrative function allows for one to appreciate a “visceral”
response to a stimulus, and hyperactivation may be involved
in a sense of disgust and social unfairness and pain. Thus,
the interaction becomes one of displeasure which needs to be
avoided, something with profoundly disorganizing effects on
the child. It should be noted that, given the essentially two-
person dynamic of dyadic attunement, the child’s response
to the mother is also responsible for activating different
maternal circuits depending on the feedback she receives
from the child. Thus, it has been shown through a functional
magnetic resonance imaging (fMRI) study that children
showing more insecure attachment behaviors will activate in
the mother, during crying episodes, activation of the amyg-
dala, parahippocampal gyrus, and insula; more specifically,
disorganized attachment behaviors will lead to the mother
decreasing activation of areas of the ventral subdivision,
including temporal areas and the sgACC [127], furthering the
challenge of attuning to a child, given the negative response
bias circuitry which becomes activated, perpetuating the
dyadic misattunement.
2.2.2. Transgenerational Transmission of “Misattuned Tem-
plate”. As mentioned, transmission of attachment schema
from adult to child has been extensively shown in the
literature. Figure 2 illustrates several areas implicated in
the maternal ability to respond to her child, and how this
information is integrated into ventral and dorsal circuitry,
which may cause a greater sense of connectedness or a feeling
Psychiatry Journal
of misattunement. The “internal working model” [128] the
child carries forth lends itself to a reenactment of what has
been learned through his or her earliest interactions, on an
affective and behavioral level. Though questions have been
posited regarding the strength of the association [129, 130],
abusive parenting and maternal insensitivity/misattunement
may be passed down from one generation to the next
[131]. In addition, abused children may grow up to display
interpersonal violence in other settings (outside the parent-
child dyad), as both abusive and abused parties [132, 133]. The
presence of a laterally biased neurocircuitry template (largely
favoring networks within the dorsal subdivision detailed
earlier) has also been demonstrated in studies of individuals
suffering abuse as a child, showing parallels with the circuitry
discussed above for the misattuned mother. Child abuse
has been associated with heightened responsiveness of the
amygdala (including for neutral stimuli) and of the insula
[134–136]. This shows the maladaptive template of sensed
environmental danger and self-identification as an unworthy
and shameful individual. There is also a hypoactivation of
areas within the ventral cortical system, thus limiting the abil-
ity to control one’s hyperarousal. Decreased activity in abused
children has been shown in areas of the temporal lobes,
hippocampus, the mPFC, the OFC, and the ventral ACC
(vACC) [134, 137, 138]. The vACC hypoactivation gives way
to preferential activity within the dACC [139]; thus, the child’s
own emotional awareness and the ability to express his or
her feelings may be impaired. In addition, abused children
show a decrease in their ability to anticipate and process
environmental cues experienced as rewarding, as demon-
strated by hypoactivation of the corpus striatum [140, 141],
impairing dopaminergically driven hedonic responsiveness.
This underlines how interpersonal reactions are experienced
as unrewarding and potentially dangerous. Corollaries can
be found in animal models; for instance, maternal separation
in rodents can lead to decreased sensitivity to opioids [142];
also, chronic social defeat can lead to a decrease in affinity
for natural rewards (e.g., sucrose solution), which is a model
for anhedonia and can develop conditioned place preference
(CPP) for low doses of cocaine (insufficient to produce CPP in
controls), showing a preference for more strongly reinforcing
substances to achieve a hedonic response [143]; these two
examples may have translational relevance regarding the
cooccurrence of psychiatric disorders with substance use.
Figure 2 outlines the transgenerational neural template of
abusive or misattuned parent-child dyads.
2.2.3. Lateral Circuitry Bias in Psychopathology. Establish-
ment of an early neural circuitry favoring the cognitive/dorsal
subdivision (with particular emphasis on the dlPFC), in lieu
of the affective/ventral one, has been shown to carry over
into later life and may inform subsequent psychopathology,
as there are similar patterns seen in a number of major
psychiatric illnesses (e.g., anxiety disorders, MDD, PTSD, and
borderline and antisocial personality disorders). In Section 4,
the pertinent neurobiology relating to these disorders will be
reviewed, as will the effects of psychotherapy on these
circuits.
9
3. Environmental Input and
Effects of Psychotherapy
This section will expand upon the genetic and circuitry
concepts discussed thus far. Particularly, the ever-dynamic
interaction between the environment and the established
epigenetic and neural footprints will be discussed and how
continued input can effect change throughout the course of
one’s life, for better or for worse, depending on how nurturing
or challenging circumstances are. It is known that EE has
been associated with hippocampal neurogenesis, particularly
in the dentate gyrus [150, 151]; there is also a demonstrable
effect of EE on synaptogenesis and dendritic branching [152].
In keeping with the concept of the importance of continued
environmental input in the face of plastic changes, it should
be noted that new hippocampal neurons require at least a
two-week period to mature before being able to contribute
to cognitive functioning [153], underlining the susceptibility
during this period and the need to take the notion of neuro-
genesis cum grano salis. This is why facilitating gene plasticity
(e.g., BDNF gene) through demethylation or creating new
neurons is not an inexorably positive change, and this is
where the concept of “differential susceptibility” becomes key,
as will be discussed.
3.1. Gene Plasticity and Epigenetic Influence. DNA methy-
lation, histone acetylation, and the presence of noncoding
RNAs are implicated in memory formation [153] and are the
target of current research to understand the influence of EE
on epigenetic markers, with consequent impact on cognitive
processes [154]. Environmental stimuli can lead to neuronal
plasticity by dynamically inducing chromatin modifications
[155].
As mentioned earlier, VTA-NAc BDNF release can have
a prodepressant effect in chronic stress. A study by Wook
Koo et al., employing a 10-day chronic social defeat stress
(CSDS) protocol in mice, showed that BDNF signaling in
the NAc is the primary mediator of CSDS-induced social
avoidance (as opposed to dopamine) [156]. This was sup-
ported by demonstrating an exacerbation of social avoidance
via phasic optogenetic stimulation of the VTA after the
defeat episodes. In addition, intra-NAc infusion of a BDNF
tyrosine receptor kinase B (TrkB) inhibitor blocked the social
avoidance induced by CSDS [156], as does local BDNF gene
knockdown in the VTA [156, 157]. The relevance of this
function factors into a model of resilience to social stress.
Resilience itself is an active process [158], and individuals
demonstrating greater tolerance to adverse environmental
stimuli have shown adaptive gene expression which quanti-
tatively can surpass the expression of the more susceptible
organisms. A study by Krishnan et al. demonstrated that mice
which were susceptible to a social defeat model of depression
showed much less of a genetic modulation as compared to
the resilient group (the latter showing greater time spent in
an interaction zone with a social target, as well as increased
sucrose preference, despite being exposed to the same social
defeat paradigm). More specifically, the resilient mice showed
increased gene expression with an upregulation of the num-
ber of membrane potassium channels in the presynaptic
10
neurons projecting from the VTA to the NAc, with a dimin-
ished release of BDNF, results which suggest a decrease in
the synaptic consolidation of the adverse response to the
defeat model [143]. This defeat model exemplifies a level of
continued negotiation of the environment in a more adaptive
way, as opposed to adopting a passive response and avoidance
after social defeat, a difference which may carry evolutionary
implications.
The impact of the environment cannot be viewed only
through the lens of the resilience-susceptibility dichotomy.
This has been shown in animal models in which the exper-
imental group has been specifically bred to demonstrate a
depressive phenotype. The study by Mehta-Raghavan used
the Wistar Kyoto strain of rats and bred them to display sus-
ceptibility genes implicating 14 transcriptomic markers which
have been associated with MDD in humans; these genes
are involved in such processes as neurodegeneration, synap-
togenesis, neuronal migration, and hippocampal excitability
[159]. The susceptible and control group (termed “more
immobile”: WMI, and “less immobile”: WLI, respectively,
depending on how they performed in the forced swim
test) were then either submitted to no intervention, chronic
restraint stress (CRS), or to EE. With regard to EE, the WMI
group showed improvement on the FST, and subsequent
mobility levels did not statistically separate from the WLI
that had no active intervention. This indicates the potentially
corrective environmental impact despite prominent genetic
susceptibility.
The translational value of animal models is intriguing and
will require further elucidation with regard to its applicability
in humans. However, it seems incontestable that one’s genetic
make-up is not entirely deterministic, and the individual’s
environment will continue to shape gene expression over
time. This paper posits that psychotherapy serves as a positive
environmental input (something akin to EE). The split model
of psychotherapy and medication management, something
which is becoming more mainstream within psychiatric prac-
tice, indicates that there is a structural dissociation within the
treatment model which may not be grounded on where the
evidence base is leading. Many patients end up only choosing
to take medications and not engage in therapy. Even those
who do psychotherapy (which may be limited to very few and
irregular encounters) may be immersed in an environment
outside the treatment setting which may be quite detrimental
and much more impactful than the work the therapist is
trying to carry out. As mentioned, even with newly generated
neurons, there is a “labile period” during which the continued
input of the environment will inform whether or not adaptive
or maladaptive memory reconsolidation will occur; in the
case of the latter, already existing dysfunctional behavior may
be exacerbated [160]. It is known that antidepressants can
lead to BDNF demethylation, thus allowing for greater gene
expression and hippocampal plasticity [161–163]. However,
the notion that medications can promote “gene plasticity”
(i.e., greater responsiveness to the environment, be it positive
or negative), as opposed to unidirectionally leading to adap-
tive changes, needs to be considered in light of the split model.
Two studies in particular have highlighted this in rodent
Psychiatry Journal
models [164, 165]. Chronically stressed mice were given long-
term treatment with fluoxetine and then exposed to either
EE or a continued stressful environment. In the EE group,
there was a decrease in depression-like behaviors, an increase
in hippocampal BDNF, and a decrease in corticosterone. In
the adverse environment group, despite being on fluoxetine,
there was a worsening in the depressive symptoms, lower
BDNF levels in the hippocampus, and higher corticosterone
levels as compared with before fluoxetine was introduced.
Thus, as has been suggested before [166], it is more important
to consider genes as plastic as opposed to seeing them
in a dichotomous manner. The human corollaries may be
expanded upon through further research. The STAR∗ D Trial
(Sequenced Treatment Alternatives to Relieve Depression)
indicated that there are environmental factors which con-
tributed to a positive response to citalopram in humans
(namely, income and employment status) [167]. Children
and adolescents who have experienced early environmental
disruption show a poorer response to fluoxetine, while those
with greater measures of family functioning have shown
greater rates of response [168]. An interesting parallel can be
seen with D-cycloserine (DCS), an NMDA agonist which can
be used as an augmentation strategy for cognitive-behavioral
as well as exposure therapy for anxiety and trauma- and
stressor-related disorders [169]. DCS can increase NMDA
plasticity and accelerate responses to treatment; however,
this can facilitate extinction or enhance consolidation of fear
memories, depending on the success of the treatment [170,
171]; thus, the patient can clinically worsen as a result of this
adjunct in suboptimal treatment settings.
This notion of genetic plasticity is at the core of dif-
ferential susceptibility. To highlight this, two of the studies
mentioned above will be discussed, both by Caspi et al. [15,
16]. In the study investigating the role of hypofunctioning
MAO-A alleles, the negative outcomes (antisocial personality
disorder, conduct disorder, conviction for violent offenses,
and disposition toward violence) only occurred in the event
of early life adversity [15]. When looking at the group that
did not suffer maltreatment, the studied outcomes pertaining
to the spectrum of antisocial behavior and personality traits
were actually found to be less than the group with the nor-
mally functioning alleles. Thus, the excess of neurotransmit-
ters conferred by the hypoactive MAO-A proved to be more
adaptive in optimal settings. While an excess of monoamines
can be associated with psychopathology, increased levels
of noradrenaline and dopamine can also be associated,
given the proper environment, with prosocial and egalitarian
behaviors, as well as with cognitive flexibility [172, 173], all of
which are diametrically opposed to typical antisocial traits.
A similar phenomenon has been described with regard to
predisposition to ADHD and MAO-A levels [174]. In a similar
vein, individuals homozygous for the 5-HTTLPR s allele
have shown more adaptive measures of social and mental
health functioning under nurturing conditions, as compared
with individuals with the l allele. Serotonin, as mentioned,
is involved with encoding of fear/threat processing; under
optimal conditions, this neurotransmitter will perform this
function in tandem with GABA and allow for adaptive
responses to the environment without an excessive arousal
Psychiatry Journal
of the fear network [22]. This is applicable to depressive
symptoms [175, 176], anxiety [176], and ADHD [20]. Thus,
how neurotransmitters are deployed will be contingent on
more permissive or limiting environmental factors. An exam-
ple of this would be that individuals with anxiety disorders
homozygous for the s allele may be more responsive to
cognitive-behavioral therapy (CBT) [177], showing a greater
ability to benefit from the environmental modifier offered;
however, this finding has been challenged by some authors
[178, 179].
Though no studies as to the knowledge of this author
have been conducted looking at the effects of psychotherapy
in interaction with genes implicated in anticipation and
processing of rewarding stimuli, they may be a target for
future research. As mentioned earlier, early life adversity can
be associated with decrease in reward sensitivity; however,
distinct patterns have been described with respect to the two
stages (i.e., anticipating and processing rewards). Functional
imaging studies have shown a decrease in basal ganglia
(BG) and ventral striatum (VS) responses during reward
anticipation [141, 180], but a greater response in these areas
during delivery of the reward [181]. Within the spectrum
of psychopathology, control individuals with impulsive traits
[182], as well as individuals with psychiatric diagnoses pre-
disposing them to impulsive actions, such as ADHD, have
shown heightened reward sensitivity and VS response to
incentives [183, 184]. Studies have aimed to understand the
effects of adversity on individuals with particular gene varia-
tions. The catechol-O-methyl transferase (COMT) enzyme is
involved in the breakdown of catecholamines. The Val158Met
polymorphism is characterized by a replacement of valine
by methionine at codon 158 on chromosome 22q11.21. Indi-
viduals homozygous for the Met allele display a decrease
in COMT function, with resultant higher synaptic PFC
dopamine levels [185, 186]. This can result in limited flexibility
in processing rewarding stimuli. Indeed, Met homozygotes
have been shown to display increased activation of the
PFC and VS when anticipating rewards [187, 188] (though
another study only found increased PFC activation) [189].
In instances of stress during childhood, Met homozygotes
displayed ACC and VS hyperactivity at reward delivery,
highlighting the gene versus environment (GxE) implications
of this polymorphism [190, 191]. Given the heightened reward
responsiveness, studies have extended to investigate whether
the association ties into psychopathology; despite no clear
association emerging between COMT and illicit substance
use per se (with the possible exception of tobacco use disor-
der) [192], increased VS activation for Met carriers parallels
the activation noted in the VS in substance users compared
to controls when positive incentives were provided [193].
Expression of this allele, in combination with childhood
adversity, may lead to a heightened pleasurable experience
when under the influence of substances, potentially increas-
ing the risk of subsequent use disorders [190, 191, 194].
Curiously, there is a decrease in reward anticipation and
increase in reward responsiveness in adolescents, with the
effects of the polymorphism showing a parallel with this
population (which seems to have more hedonically drive and
consummatory behaviors) [195, 196].
11
The dopamine receptor 4 (DRD4) is part of the D2-like
family of dopamine receptors and contains seven transmem-
brane domains; it has been shown to be present in the meso-
corticolimbic pathway, being thus implicated in cue reactivity
and in the reward pathway [197]. The DRD4 variable number
of tandem repeats (VNTR) polymorphism (exon 3) has also
been a subject of attention with regard to GxE interactions as
they pertain to the reward system. This VNTR is suggested
to be implicated in downstream changes in cyclic adenosine
monophosphate (cAMP) expression [198]; more specifically,
the long (L) allele is associated with a decrease in ligand
binding and reduced cAMP formation when dopamine binds
to the receptor [198, 199]. The L allele is thus associated with
a decrease in mesocorticolimbic dopaminergic transmission,
resulting in increased craving and arousal to cues relating to
potential rewards [197, 200]. These individuals have shown,
when raised in conditions of socioeconomic disadvantage, to
prefer smaller immediate rewards over those that are larger
and more delayed, highlighting the interaction with adverse
environmental influences as it relates to reward sensitivity;
the differential susceptibility factor has been highlighted by
the greater appreciation of future rewards of people with this
polymorphism in the absence of adversity [201].
3.2. Epigenetic Changes Observed with Psychotherapy. Given
the established importance of continued environmental input
on epigenetic modifications, research has begun to emerge on
such changes as they relate to the effects of psychotherapeutic
interventions. Some of the genes discussed previously in this
paper have been the target of these research efforts, and
these studies will be reviewed in more detail. Importantly,
while some forms of psychotherapy will be mentioned in
this section, they will be elaborated on in greater detail in
Section 4.
Methylation of the BDNF gene has been associated with
BPD [202], particularly given this disorder’s high rate of
childhood abuse. Dialectical behavioral therapy (DBT) has
a strong evidence base for treating this condition, and the
effects of DBT on BDNF gene methylation have been assessed
(DBT will be described in greater detail later) [51]. In this
study, 115 patients were assessed after four weeks of DBT.
Nonresponders showed an increase in methylation of the
BDNF gene exons I and IV (as assessed by bisulfite treatment;
DNA was extracted from leukocytes), while responders
showed a decrease in methylation; these results held when
adjusted for medication effects (all patients in the study were
medicated concurrently). Decreases in methylation corre-
lated with symptomatic improvement (depressive symptoms,
hopelessness, and impulsivity); on the depression scale, only
those with greater than 70% improvement (as assessed by
the Beck Depression Inventory II) showed a statistically
significant decrease in methylation.
Prolonged exposure (PE) is an intensive structured psy-
chotherapy utilized for PTSD [203] (refer to description later
in this paper). One study looked at the predictive value of GR
NR3C1 (exon 1F) and FKBP5 methylation on the response to
12 weeks of PE in patients with PTSD [204], as well as the
response-methylation correlation after treatment (peripheral
mononuclear cells were utilized). Higher pretreatment levels
12
of GR methylation were associated with greater response
to PE. In contrast, there was no clear predictive value of
pretreatment FKBP5 methylation on response outcomes.
Treatment responders showed a negative correlation between
GR 1F methylation and self-reported PTSD symptoms.
Conversely, they displayed a correlation between decreased
FKBP5 methylation and lower scores on the Clinician-
Assisted PTSD Scale (CAPS) after treatment. Both of these
epigenetic changes correlated with an elevation in cortisol
levels posttreatment. It has been demonstrated that clinical
response to brief eclectic psychotherapy in patients with
PTSD can lead to an increase in cortisol levels [205], show-
ing a neuroendocrine parallel with the epigenetic changes
outlined. While improvement in symptomatology may be
associated with a decrease in cortisol reactivity [206] (high
reactive levels being associated with consolidation of trau-
matic memories) [207], higher baseline levels of cortisol may
be more adaptive in PTSD given the mitigating effect of
cortisol on release of norepinephrine (NE) from the locus
coeruleus.
In a study employing CBT to treat panic disorder, MAO-A
gene methylation was analyzed (in blood cells) with regard to
treatment response [208]. Panic disorder has been associated
with hypomethylation (hence greater expression) of this gene
[209], with an inverse correlation found between methylation
and symptom severity [208]. In the Ziegler et al. study [208],
after six weeks of therapy, responders were shown to have
increased methylation of the MAO-A gene (reaching levels
similar to controls), while nonresponders showed further
demethylation. From a neurobiological standpoint, the excess
of serotonin which would result from increased methylation
of MAO-A would serve to decrease the activation of areas
of the brain involved in the avoidance and fear responses, as
well as in the heightened autonomic response characteristic
of panic attacks, such as the dorsal PAG [210]; this would
allow for more rostral areas (e.g., PFC, septum-hippocampus,
and amygdala) to be activated and facilitate a more adaptive
response [211].
Expanding the discussion surrounding SERT and epige-
netic modifications, a study was conducted to assess how CBT
would affect transporter methylation in children with anxiety
disorders (buccal swabs were performed for DNA collection)
[212]. SERT methylation has been associated with adverse life
events, including child abuse [213, 214] and, as mentioned,
expression of this transporter (with its consequent impact on
serotonin availability) can impact how responsive an individ-
ual will be to psychological treatments [177]. Most patients in
the Roberts et al. study were diagnosed with generalized anxi-
ety disorder (GAD); responders showed a nonstatistically sig-
nificant increase in SERT methylation, while nonresponders
showed a significant decrease in methylation (𝑝 = 0.037).
Interestingly, the authors conducted a follow-up assessment
six months after the treatment was completed, and there
was a significant increase in methylation for participants that
continued to show symptom improvement during this time
period (an indicator of consolidated learning) as compared
to those that showed no improvement or worsened (𝑝 =
0.003). Thus, at follow-up, there was a significant difference
in SERT methylation between responders (increase) and
Psychiatry Journal
nonresponders (decrease). The parallel traced is between a
higher SERT DNA methylation (which replicates the s allele
of the 5-HTTLPR) and greater responsiveness to treatment;
the lower the expression of the gene, the greater the individual
would be able to respond to the positive environmental
input, and the epigenetic modifications seen with successful
treatment would seem to facilitate this potential for continued
improvement.
Controversy remains about the value of measuring
methylation changes in specific genes as an indicator of
treatment response; it has been questioned what the value
is of assessing methylation in peripheral tissue. It has
been challenging to demonstrate direct correlations between
peripheral blood cell and brain methylation [208, 209].
However, MAO-A gene methylation in leukocytes has been
shown to be inversely correlated with MAO-A levels in the
brain [208, 215], highlighting the utility of this measurement.
Also, authors have argued that, with regard to buccal tissue,
the lower cell heterogeneity and a degree of developmental
commonality with brain tissue would make it a promising
option for methylation studies [216]. This burgeoning field
will hopefully continue to yield elucidating data.
4. Changing Default Neural
Circuitry Activation
One change that can be fostered by psychotherapy is modi-
fication of default activation patterns involving the circuitry
described before. Resting-state functional connectivity and
task-related functional imaging have increased understand-
ing of how particular areas of the brain can maintain
maladaptive modes of thinking and behaving, as well as the
implications of medication and psychotherapeutic treatment
strategies in reconfiguring connectivity in tandem with clin-
ical improvement or lack thereof. Dorsal or ventral bias can
inform more or less functional connectivity with subcortical
areas and also underlie the degree of flexibility that can be
elicited when interacting with particular stimuli. Though the
dlPFC may be anomalously and excessively activated in mal-
adaptive cognitive appraisal, it is, along with the hippocam-
pus, also one of the key areas of the brain that will need to be
accessed to allow for psychotherapy to be effective [217], given
that the content of one’s ruminations and fixations need
to be allowed room for exploration in order to promote
flexibility and for an understanding of one’s preoccupations
to be processed and worked through. This would potentially
allow for a greater fluidity between emotional appraisal and
regulation, the latter implicating ventral structures (including
the vmPFC), which in itself allows for a more measured
control of subcortical activation [99, 218]. The vmPFC is
paramount in the therapeutic response, given evidence that
only engaging dlPFC and other lateral PFC regions may
not be sufficient to mitigate amygdala reactivity to negative
stimuli [219]. The hippocampus will allow for contextual
consolidation of the response to treatment. Importantly,
certain activation patterns, though involved in particular
symptom spectra, may also be prognostic indicators of a
positive response to treatment, as engaging these areas while
Psychiatry Journal
working therapeutically may help to reconfigure their role
within the neural circuit. For instance, ability to engage
the hippocampus, which gauges the potential to provide
greater contextual input to counter generalizations in belief
and response patterns, has been shown to predict treatment
response to CBT in adults with panic disorder (PD) and
GAD [220]. The neuroimaging literature of psychotherapy
will be reviewed in this section, focusing mainly on the effects
of psychotherapy on conditions in which bias favoring the
dorsal system is well established (anxiety disorders, MDD,
PTSD, and BPD). A brief review of neurobiology will be
provided prior to describing the effects of different forms of
psychotherapy. Tables 1–3 provide a synthesis of the studies
outlined.
4.1. Neurobiology of Conditions with Lateral/Dorsal Bias
4.1.1. Anxiety Disorders. In the setting of anxiety, there is
a bias in an individual’s interpretation of the environment
[107, 221], with a heightened perception of threat, a decreased
recruitment of the PFC during emotionally regulated tasks
[222], and an increase in amygdala and anterior insula
responsiveness. Consequently, there is a difficulty in the gen-
eration of different outlooks on a given situation [223], thus
the maladaptive response feeds into itself, and the “bottom-
up” response is maintained [224]. Altered patterns of func-
tional connectivity occur in corticocortical and cortical-
subcortical networks (e.g., increased amygdala-dACC and
decreased mPFC-OFC connectivity) [211, 225, 226], in tan-
dem with preferred activation of cortical areas favoring rumi-
nation, negative affective cognitions, and decreased cognitive
appraisal (e.g., dlPFC and inferior frontal gyrus (IFG)) [218,
227–230]. As a result, the anxious individual has an atten-
tional bias and difficulty disengaging from threatening stim-
uli, magnifying the cognitive inflexibility and leading to over-
generalization [228]. This is seen pervasively in GAD, which
is associated with persistent anxiety symptoms, leading to
autonomic arousal and diffuse preoccupations and ruminat-
ing about numerous situations in an individual’s life, without
necessarily being attached to circumscribed cues, as in pho-
bias. Excessive attention to social cues and rumination about
environmental stimuli, as seen in social anxiety disorder
(SAD), have also been associated with increased connectivity
between the amygdala and more dorsal areas of the PFC,
with a concurrent decrease in amygdala-vmPFC connectivity
[231, 232]. As stimuli become more proximal, activation of
fear-system components will move from lateral to central
amygdala, with subsequent activation of PAG and brainstem
nuclei, inducing a more pronounced panic response [233]. Of
note, phobic disorders and PD are variably associated with
increased activity in the CeA, insula, and PAG [234–236].
4.1.2. Major Depressive Disorder. MDD has been associated
with greater activity in areas of the brain associated with the
processing of emotionally salient stimuli, including the amyg-
dala and sgACC [237–240]. The amygdala may also lose its
ability to discriminate between neutral and emotional stimuli
[241]. Decreased volumes in the hippocampus, BG, and in
the OFC have also been demonstrated [242]. The dlPFC can
13
show increased or decreased activation, depending on the
function which is being assessed. With the ruminative and
poor self-view aspects, as well as the negativity bias toward
external stimuli, there is an increase in dlPFC activity [108,
241, 243, 244]. This is compounded by the concurrent vmPFC
hypoactivation [109, 241], which contributes to difficulty
with reappraisal of negative thoughts. However, the dlPFC
is underrecruited when the tasks involve frame shifting and
inhibition, executive control, and planning [222, 245, 246].
There may also be differences between right and left dlPFC
activation in MDD depending on the affective valence of
decision-making processes [247]. Decrease in frontostri-
atal responsiveness to reward has been described; this
includes decreased anticipation and enjoyment of rewarding
objects/stimuli, as well as a bias towards overestimating
failure [248–250]. In MDD, there is also difficulty in main-
taining activation in the NAc during attempts to consciously
upregulate positive emotions [251].
4.1.3. Posttraumatic Stress Disorder. In PTSD, one of the
most described neurobiological findings is a decrease in the
volume of the hippocampus [252]. There is an increase in
activity in the amygdala (leading to kindled fear acquisition
networks) and in the insula [253], as well as an increase
in hippocampal activity when encoding negatively valenced
stimuli [254]. Sensitization of the dACC is associated with an
increase in the appraisal of threat and expression of fear and
correlates with the heightened activation of the insula and
amygdala [101, 255]. Difficulty with modifying this response
pattern derives from hypoactivation of the rACC, vmPFC and
of the hippocampus during fear extinction [255].
4.1.4. Borderline Personality Disorder. Cluster B personal-
ity disorders, in particular BPD and antisocial personality
disorder (ASPD), are associated with heightened affective
responses to the environment with behavioral overswings
without PFC modulation; it is important to highlight that,
in the case of ASPD, this applies to cases more commonly
associated with child abuse and in which violence is reactive
as opposed to proactive, the latter being associated with psy-
chopathic traits, and thus with different patterns of emotional
reactivity and autonomic arousal [256, 257]. Both of these
personality disorders have been associated with heightened
amygdala reactivity, as well as a decrease in vmPFC, reflecting
the difficulty in identifying emotional states in others that are
not inflexibly perceived as menacing [257–259]. Also, in BPD
there is enhanced connectivity between the dACC and the
amygdala and insula, heightening focus on social cues with
individually ascribed salience [260].
In the following section, different forms of psychotherapy
and their effects on the described circuits will be described in
greater detail.
4.2. Psychotherapeutic Modalities and
Effects on Neurocircuitry
4.2.1. Cognitive-Behavioral Therapy (CBT). CBT is a typically
time-limited form of treatment which involves cognitive
14 Psychiatry Journal

Table 1
(a) Description of psychotherapy and neuroimaging studies: CBT for anxiety disorders∗ .

Number of
patients
Diagnosis Study Design Treatment effects of psychotherapy
(intervention
group)
Normalization of hyperactivation in IFG.
Greater connectivity between IFG and:
Kircher et al. 42 fMRI amygdala, hippocampus, ACC, mPFC, and
(2013) (unmedicated) 12 weeks of CBT lPFC
Decrease in activation in the amygdala,
anterior insula, dACC, rACC, and vmPFC
Normalized hyperactivation of pgACC and
PD fMRI amygdala. Increase in hippocampal
Lueken et al. 49
12 sessions of CBT (twice-weekly for six activation with stimulus contingency
(2013) (unmedicated)
weeks) processing
Enhanced ACC-amygdala coupling
fMRI In therapist-guided group, there was an
Straube et al.
42 12 sessions of manualized CBT increase in activation of the hippocampus,
(2014)
(unmedicated) Patient-guided and therapist-guided as well as a decreased connectivity between
[144]
protocols were compared left IFG and left hippocampus
CBT group: decrease in limbic, paralimbic,
and PAG hyperactivation. Results
maintained at one-year follow-up (multiple
PET scan
brain areas needed to be included to reach
Furmark et al. 18 CBT for eight weeks (each session was 3
SoP statistical significance).
(2002) (unmedicated) hours)
Citalopram group: decrease in thalamic
Compared with citalopram-only group
hyperactivation (suggesting decreased
sensory input into the amygdala); decrease
in vPFC activation
Paquette et al. 12 fMRI Decrease in activation in dlPFC and
(2003) (unmedicated) 4 sessions parahippocampal gyrus
Anticipation: decreased cerebral blood flow
fMRI (CBF) in bilateral parahippocampal gyri,
SP Soravia et al. Unspecified number of CBT sessions ventral anterior thalamus, Brodmann area 8,
8 (unmedicated)
(2016) (though scanning done one month after and the ACC
treatment started) Postprocessing phase: reduced CBF in the
bilateral insula and motor cortex.
Straube et al. 28 (unclear if fMRI
Decrease in activation in ACC and insula
(2006) medicated) 2 sessions (4-5 hours each)
fMRI
Maslowsky et al. 8 weeks of CBT Increase in activation in vlPFC to angry
7 (unmedicated)
(2010) Comparison group was patients on faces
fluoxetine
12
(unmedicated)
McClure et al. fMRI Decrease in amygdala activity (not
(3 with a
(2007) 8 weeks of CBT statistically significant)
diagnosis of
social phobia)
GAD
Before treatment, patients showed blunted
responses to positive faces in the amygdala,
insula, and ACC; they also showed
heightened amygdala-insula and
Fonzo et al. 21 fMRI amygdala-precuneus connectivity
(2014) (unmedicated) 10 sessions of CBT After treatment: decrease in activation to
angry and fearful tasks in the sgACC and
amygdala.
Increase in activation to happy tasks in the
anterior and posterior insula
Psychiatry Journal 15

(a) Continued.

Number of
patients
Diagnosis Study Design Treatment effects of psychotherapy
(intervention
group)
Activation changes in areas of lPFC, vPFC,
Doehrmann et 39 fMRI
and in the amygdala, none statistically
al. (2013) (unmedicated) 12 weeks of CBT
significant
Cognitive reappraisal of negative self-beliefs
was parameter assessed. Amygdala reactivity
Goldin et al. 75 fMRI
to negative self-beliefs remained consistent
(2013) (unmedicated) 16 sessions of CBT
over time
Increase in the dmPFC and dlPFC
Increase in the superior frontal gyrus,
middle occipital lobe, and inferior parietal
SAD
lobule activity when reacting to social praise
Goldin et al. 59 fMRI
Increases in right superior frontal gyrus and
(2014) (unmedicated) 16 weeks of CBT
inferior parietal lobule, and decreases in left
posterior superior temporal gyrus when
reacting to social criticism
14 (2 on
No significant correlation between symptom
Klumpp et al. bupropion, the fMRI
improvement and activation patterns in
(2013) rest 12 weeks of CBT
dmPFC or mPFC
unmedicated)
Yuan et al. 15 (4 on stable fMRI Attenuation of dACC-amygdala and
(2016) doses of SSRIs) 8 weeks of group CBT dmPFC-amygdala connectivity
∗
The following legend serves as a guide for all the tables in this paper.
d = dorsal; dl = dorsolateral; dm = dorsomedial; l = lateral; m = medial; pg = pregenual; r = rostral; sg = subgenual; v = ventral; vl = ventrolateral; vm =
ventromedial.
ACC = anterior cingulate cortex; AG = agoraphobia; BATD = behavioral activation treatment for depression; BDI = Beck Depression Inventory; BG = basal
ganglia; CAPS = clinician-administered PTSD scale; CBT = cognitive-behavioral therapy; DBT = dialectical behavioral therapy; EMDR = eye movement
desensitization and reprocessing; fMRI = functional magnetic resonance imaging; GAD = generalized anxiety disorder; IFG = inferior frontal gyrus; MDD =
major depressive disorder; OFC = orbitofrontal cortex; PAG = periaqueductal gray; PCC = posterior cingulate cortex; PD = panic disorder; PET = positron-
emission tomography; PFC = prefrontal cortex; PTSD = posttraumatic stress disorder; rCBF = resting cerebral blood flow; SAD = social anxiety disorder;
SERT = serotonin transporter; SoP = social phobia; SP = specific phobia; SPECT = single-photon emission computed tomography; SSRIs = selective serotonin
reuptake inhibitors.

(b) Description of psychotherapy and neuroimaging studies: CBT for major depressive disorder.

Number of
patients
Diagnosis Study Design Treatment effects of psychotherapy
(intervention
group)
SPECT
Amsterdam et 20 Increase in standardized uptake ratio in the midbrain
12 weeks of CBT (twice weekly
al. (2013) (unmedicated) and bilaterally in the medial temporal lobes
for four weeks, then weekly)
Less amygdala hyperactivity when exposed to sad faces.
16 fMRI
Fu et al. (2008) Normalization of amygdala-hippocampus activation
(unmedicated) 16 sessions of CBT
pattern
17 PET Increased activity in dACC, hippocampus, and
Goldapple et al. (unmedicated; 15–20 sessions of CBT parahippocampal gyrus activity
MDD (2004) 14 completed Comparison group was on Decreased frontal cortical activity mainly in the dlPFC
protocol) paroxetine and OFC
PET
16 weeks of CBT (at least 8 weeks
Decrease in metabolism bilaterally in the PCC
of treatment completed prior to
Kennedy et al. 12 (opposite to venlafaxine group), OFC, and in the left
rescanning; all but one patient
(2007) (unmedicated) dmPFC. Increase in metabolism in the right inferior
completed 16 weeks)
occipital cortex, in the sgACC, and in the vmPFC
Comparison group treated with
venlafaxine
16 Psychiatry Journal

(b) Continued.

Number of
patients
Diagnosis Study Design Treatment effects of psychotherapy
(intervention
group)
10 (1 medicated, fMRI
Klein et al. stable dose of 12 weeks of CBASP∗ (mean
(2014) venlafaxine for number of sessions was 15.8; each
months) session was 50 minutes)
15
(unmedicated) fMRI
Ritchey et al.
Data from 11 Weekly CBT sessions (average of Increase in vmPFC activity
(2011)
patients was 20.7 sessions and 30.3 weeks)
used
Decreased parahippocampal activity
Sankar et al. 16 fMRI
Increased activity in hippocampus, precentral gyrus,
(2015) (unmedicated) 16 weeks of CBT
inferior parietal lobe, and precuneus
Straub et al. 18 fMRI Decrease in bilateral amygdala, hippocampus, and
(2015) (unmedicated) 5 sessions of group CBT sgACC activity
23 (all on stable
doses of Activity during self-referential processing in vACC and
Yoshimura et al. fMRI
antidepressants mPFC was increased for positive stimuli and decreased
(2014) 12 weekly sessions of group CBT
for at least 8 for negative stimuli
weeks)
29 (all on stable
doses of fMRI
Yoshimura et al. Decrease in dysfunctional mPFC-ACC connectivity
antidepressants 12 weekly (90-minute) CBT
(2017) correlated with improvement on BDI score
for at least 8 sessions
weeks)
∗
CBASP = cognitive behavioral analysis system of psychotherapy.

(c) Description of psychotherapy and neuroimaging studies: CBT for posttraumatic stress disorder.

Number of
patients
Diagnosis Study Design Treatment effects of psychotherapy
(intervention
group)
14
(7 considered
fMRI After treatment, the CAPS score was
Bryant et al. treatment
8 weeks of CBT (including imagined and in positively correlated with amygdala and
(2008) responders, 3 of
vivo exposure) ACC activity
which were on
PTSD psychotropics)
29
(some on stable
Thomaes et al. fMRI Decrease in activation in anterior insula and
doses of SSRIs
(2012) 20 weekly sessions (group CBT) dACC to emotional Stroop
or benzodi-
azepines)

distortion analysis (including overgeneralizing and catas-
trophic thinking), situational reappraisal, exposure hierarchy
analysis, and several exposure components. It has a strong
evidence base for numerous psychiatric conditions, including
various anxiety disorders as well as MDD [261]. Tasks utilized
to assess efficacy of CBT attempt to replicate stimuli within an
individual’s life which may elicit more generalized or specific
fear-based responses. It is at the core of CBT to attempt a
reworking of cognitive schema, accessing more flexible cor-
tical areas which may allay conditioned responses through
inhibitory connections to subcortical areas. Tables 1(a), 1(b),
and 1(c) detail the neuroimaging studies assessing neural
markers of treatment response.
(1) CBT for Anxiety Disorders. CBT can address both the more
ruminative/cognitive-based symptoms of anxiety disorders
(as generated by diminished activation in medial PFC and
areas of the ACC, with ineffective control of amygdala
responses) as well as the more proximal fear-based responses
(as outlined for phobias and panic disorder). Several studies
have aimed at assessing the PFC-amygdala activation patterns
in response to treatment; this has been done through subject
 Table 2: Description of psychotherapy and neuroimaging studies: miscellaneous psychotherapies.
Number of patients
Psychiatry Journal

Modality of psychotherapy Diagnosis Study (intervention Design Treatment effects of psychotherapy

group)
MRI
Bossini et al. (2011) 9 (unmedicated) 12 weeks (weekly Bilateral volume increase in the hippocampus
Eye movement
90-minute sessions)
desensitization and PTSD
SPECT Decreased tracer uptake in medial temporal cortex
reprocessing (EMDR)
Pagani et al. (2007) 15 (unmedicated) 8 weeks (five 90-minute (uncus), hippocampus, occipitotemporal cortex, and
sessions) visual cortex (BA 17)
fMRI
8
Felmingham et al. 8 weeks of treatment Increase in rACC activity and a decrease in bilateral
(2 on SSRIs; the
(2007) (cognitive restructuring amygdala activity
Prolonged exposure (PE) PTSD rest unmedicated)
with imaginal exposure)
Helpman et al. 16 fMRI Decrease in rACC activation and increased activity in
(2016) (unmedicated) 10-week PE protocol the mPFC
Brief eclectic Lindauer et al. 20 SPECT Decrease in rCBF in the right uncus
PTSD
psychotherapy (BEP) (2008) (unmedicated) 16 weekly sessions Increase in rCBF in the left superior temporal gyrus
fMRI Increase in regional homogeneity in the vmPFC and
Guided imagery MDD Huang et al. (2014) 23 (unmedicated)
5 weeks of treatment ACC
PET
Brody et al. (2001) 39 12 weeks of CBT Increased activity in the dlPFC and dACC
[145] (unmedicated) (comparison group Decrease in activity in the vACC and anterior insula
received paroxetine)
PET
Reduced activity in lateral PFC, caudate, thalamus, left
Interpersonal Brody et al. (2001) 24 12 weeks of IPT
MDD ACC Increased activity in left temporal lobe
psychotherapy (IPT) [146] (unmedicated) Comparison group received
paroxetine
SPECT
Up to 16 hour-long weekly
Martin et al. (2011) 10 (unmedicated) sessions Increased blood flow in right BG and right PCC
(comparison group was
treated with venlafaxine)
Goodman et al. 11 fMRI
Decrease in amygdala activation to unpleasant images
(2014) (unmedicated) 12 months of DBT
Dialectical behavioral fMRI
BPD 8
therapy (DBT) 12 weeks of DBT; amygdala Increased connectivity between vmPFC and amygdala
Paret et al. (2016) (all patients on
neurofeedback (NF) (did not persist without NF component)
medications)
incorporated for 4 sessions
17
 18

Table 3: Description of psychotherapy and neuroimaging studies: psychodynamic psychotherapy.

Number of patients
Diagnosis Study Design Treatment effects of psychotherapy
(intervention group)
fMRI Decreased limbic and increased vPFC and OFC activity
PD Beutel et al. (2010) 9
4 weeks (inpatient setting) Parameter was emotional linguistic go/no-go task
fMRI Decrease in amygdala, dmPFC, and sgACC
Buchheim et al. (2012) 16 (unmedicated)
15 months hyperactivity
PET
Greater binding of 5-HT1A in the medial PFC and in
Karlsson et al. (2010) 8 (unmedicated) 16 weeks of therapy
the OFC
Comparison group received fluoxetine
PET
9 (treatment completers; all 16 weeks of dynamic therapy using the
Roffman et al. (2014) Decrease in metabolism of right insula
on antidepressants) Core Conflictual Relationship Theme
MDD manual
1
(unmedicated)
SPECT
Viinamäki et al. (1998) (Likely comorbid SERT density normalization within the mPFC
Weekly therapy for 1 year
borderline personality
disorder)
Decrease in BG and amygdala hyperactivity to
18 fMRI
Wiswede et al. (2014) operationalized psychodynamic diagnostics (OPD)
(unmedicated) 8 months
sentences
5 enrolled
SPECT
BPD Lai et al. (2007) (2 completed) Increased perfusion in frontal cortical areas
Weekly for 16 months
(unmedicated)
Psychiatry Journal
Psychiatry Journal
responses to emotional faces [262–264]; posttreatment effects
demonstrated a decrease in activation of the amygdala [262,
263], as well as within the sgACC (which can inform dlPFC
activity) [263], with more ventrally favored pathways being
recruited; one study showed posttreatment activation of the
ventrolateral PFC (vlPFC) when exposed to angry faces (this
area also aids in top-down control of the amygdala) [264].
Stimulus processing in anxiety disorders can be excessively
influenced by amygdala input; CBT, through response pattern
recognition and gradual incorporation of contextual data into
one’s appraisal of the environment, increases hippocampal
activation, allowing for a more nuanced and cognitively
informed processing to take place [265].
SAD can be considered a condition which factors in
both the cognitive/distal and subcortical/proximal elements
of anxiety and fear responses, as the reality of exposure
occurs alongside pronounced ruminative processing. The
importance of the cognitive component is of particular rele-
vance when reviewing results in the literature for the efficacy
of CBT, as there have been some varying findings, par-
ticularly pertaining to subcortical elements. Attenuation of
enhanced dACC-amygdala and dorsomedial PFC- (dmPFC-)
amygdala connectivity [226] was demonstrated in one CBT
study, suggesting a more flexible top-down control. In
contrast, another study showed that amygdala reactivity to
negative self-beliefs remained consistent over time in the
treatment group [266]; there was an increase in areas of
the dorsal PFC (namely, dmPFC and dlPFC). The authors
stressed the importance of these areas specifically in cognitive
reappraisal, as opposed to areas of the brain involved in fear
extinction. Another individual CBT study assessed the effects
of treatment on emotional responsivity to social evaluation
[267]. Interestingly, as with the study before, improvement
in negative emotions when reappraising social criticism was
associated with activation in mainly cognitive as opposed
to more effectively attuned cortical areas as a result of the
treatment. Increased hippocampal activation and a decrease
in dysfunctional IFG-hippocampal connectivity was noted
with therapist-guided CBT in panic disorder patients (as
compared with self-guided treatment), suggesting cognitive
reframing and increased contingency encoding may be facil-
itated by the therapeutic dyad [144].
With regard to more proximal fear response patterns,
CBT has been shown to decrease limbic, paralimbic, and PAG
hyperactivation in a public speech task, with maintenance of
effects at one-year follow-up [236]; when exposed to a specific
phobic stimulus (e.g., a spider), CBT can additionally pro-
mote a decrease in dlPFC and insula activation, highlighting
the decrease in autonomic fear systems as well as activity in
areas implicated in disgust and shame. A decrease in insula
activity during fear processing was supported by an addi-
tional study of spider phobia in patients undergoing group
CBT with an exposure component [268]. In the treatment of
PD, CBT has been shown to decrease activation within fear-
based networks (e.g., amygdala, anterior insulae, and dACC),
as well as promoting more harmonious circuit connectivity.
The latter is exemplified by normalization of hyperactivation
in the IFG [230], as well as greater connectivity between the
latter and the amygdala, hippocampus, ACC, and medial and
19
lateral PFC, informing a more affectively informed and less
cognitively controlled circuitry. In the cited study, treatment
also resulted in a decrease in activation of the vmPFC, which
may suggest a more integrated form of decreasing subcortical
hyperactivity by deploying other areas of the extinction
circuitry.
(2) CBT for Major Depressive Disorder. CBT is arguably
the most well-validated form of psychotherapy for MDD
(showing potential effectiveness over 50% of cases) [261],
though evidence has supported combination treatment (with
either medication or other modalities of therapy) [269, 270].
There are many studies which have gauged predictive and
outcome findings relating to psychotherapy for MDD, and the
effects of CBT on neural circuits in MDD are multifaceted
and still an area of active research. There is some level of
controversy surrounding how activity in given areas fits into
the framework of this condition, and this will be discussed
below.
As mentioned, changes in emotional stimulus discrimi-
nation in the amygdala and portions of the ACC, decreased
input from the hippocampus, alterations in reward process-
ing, and biased PFC recruitment are relevant in the clinical
presentation of MDD. As such, the patterns of PFC, cingulate,
and amygdala-hippocampal activation are the prime regions
of interest throughout the studies analyzed. As noted in
anxiety disorders, CBT can result in a strengthening of
contextual appreciation of stimuli, with normalization of the
amygdala-hippocampus activation pattern and less amygdala
hyperactivity when exposed to emotional faces [240] (though
it is important to highlight some level of functional het-
erogeneity within the amygdala, as evinced by therapeutic
response leading to heightened activity to implicit processing
of emotions) [271]. Modification of activation patterns with
CBT also occurs in other areas involved with processing
of emotionally salient stimuli, such as the precuneus and
inferior parietal lobule [272]. The trend towards activating
more ventral portions of the cingulate and PFC has also been
demonstrated with CBT. One PET study comparing CBT to
venlafaxine showed that treatment response correlated with
a decrease in dorsal areas of the cingulate cortex (namely, the
PCC) and with a metabolic increase in the anterior portion
of the sgACC and vmPFC [273], indicating greater top-down
regulatory function (this is particularly relevant given that
activity in the sgACC has been associated with depression
severity, as this area in MDD can show decreased volume)
[274]. The increase in mPFC activity has been replicated
elsewhere [241, 275]. Response to treatment has also been
associated with a decrease in metabolism in the OFC [273,
276], which may indicate an increase in flexibility in terms of
the fixity of salience ascribed to stimuli, given that the OFC
can contribute to establishing affectively biased perceptions
[273]; in line with this, it has been hypothesized that the
increase in OFC activity in MDD is a compensatory mecha-
nism owing to an attempt to regulate amygdala hyperactivity,
given the decrease in sgACC/vmPFC regulatory mechanisms
[274]. The decrease in dmPFC activity shown in this study
[273] after CBT is also of relevance given that this corti-
cal area is involved in self-referential aspects of emotional
20
stimulus processing, incorporating elements of ascribing
meaning to emotional experiences and recall of affect-laden
past events, and again a decrease in activation may reflect
greater cognitive and self-assessment flexibility. Other dorsal
cortical areas (e.g., dlPFC) have been shown to decrease their
excessive activity in response to treatment, in tandem with
increased hippocampal and parahippocampal activity [276],
again reinforcing the more harmonious PFC network as con-
textual input is allowed through revisiting ingrained thinking
patterns. It should be noted that modification within cortical
circuitry (without engaging limbic structures) can lead to
clinical change. In one study [272], there was a significant
positive correlation between symptom improvement and left
precentral gyrus activity, a brain region involved in successful
response inhibition, which may be impaired in MDD [277].
Interestingly, in this study, there was not an observable
engagement in the amygdala, something which was felt to
be due to the cognitively effortful nature of accessing and
working with dysfunctional thoughts, an activity which may
be more circumscribed to cortical areas; thus, this would
be one instance in which the “medialization” phenomenon
(given the dorsal and lateral localization of the structure) and
greater cortical-subcortical connectivity would be bypassed,
though still with clinically relevant effects.
It does need to be emphasized that these different brain
regions are not uniquely ascribed discrete functions, as our
understanding of functional connectivity has evolved. As
such, while certain patterns can be noted in the conditions
outlined, there may be variations depending on compen-
satory activation of other networks. One example of such
is the parahippocampal gyrus in MDD. This brain area, as
the hippocampus, is associated with episodic and contextual
memory, assisting as well in the associative learning of pos-
itively and negatively valenced experiences, and activation
is greater with novel as opposed to familiar tasks. Increased
activity in this area in response to treatment may indicate
incorporation of new information and modes of thinking,
linking contextual input with new modes of understanding
one’s cognitive schemas [276]. Parahippocampal activation
can also be associated with dysfunctional attitudes and neg-
ative beliefs; thus, in reworking these through CBT, activity
can be decreased in this area over time [272]. Sankar et
al. posited that this occurred due to a decrease in extreme
negative thoughts in the treatment group as well as an
increased familiarity with the material being accessed (it
is of note that a similar decrease occurred in the control
group, indicating this gradual assimilation of material and the
lessening of parahippocampal activity is functional) [272].
Another example relates to increased activity of dorsal areas
of the cingulate in response to treatment, such as the dACC
and PCC (the latter also having reciprocal connections with
the dlPFC; the reader is referred to the section on interper-
sonal psychotherapy for discussion of increased activation
of the PCC) [276, 278, 279]; this finding may underscore
activation of dorsal PFC regions during CBT in order to
access and revisit more inflexible thinking patterns; thus,
there is not uniformity in the finding of decreased dACC
Psychiatry Journal
activity with successful treatment, though again this may be
adaptive.
With regard to the reward pathway, it has been mentioned
that patients with MDD have difficulty predicting positive
outcomes to potentially rewarding situations. One adolescent
study of group CBT assessed response to treatment through
its effects on a reward paradigm [280]. Successful treatment
resulted in a decrease in bilateral amygdala, hippocampus,
and sgACC activity. The authors associated the sgACC
hyperactivity with predicting treatment response (see further
discussion regarding neural predictors of response later in
this paper) and emphasized its role in erratic processing of
stimuli, which may lead to poor self-views and impaired
ability to appreciate positive stimuli. Behavioral activation
therapy has also resulted in greater engagement of the VS and
precentral gyrus during anticipation of rewards and of the
OFC during reward feedback [281].
(3) CBT for Posttraumatic Stress Disorder. The revisiting
of traumatically informed cognitive beliefs can be done
through multiple therapeutic modalities (see further discus-
sion below), many of which incorporate elements of CBT. The
neurobiology of PTSD is marked by heightened activation
of the amygdala-dACC network, as well as of the insula,
with little room for contextual hippocampal input. Successful
CBT has been shown to effect a decrease in hyperactivation
within the amygdala [282], dACC, and anterior insula [283],
allowing for enhanced cognitive appraisal.
(4) Dialectical Behavioral Therapy (DBT). Both BPD and
ASPD, as mentioned, are associated with decreased function-
ing of the vmPFC, interfering with empathic attunement and
ability to safely regulate affective arousal when confronted
with social cues. DBT is an integrative approach which has
been gaining evidence in the treatment of BPD [284]; it
consists of both individual and group processes and integrates
elements of CBT as well as mindfulness, aiding in distress
tolerance, cognitive reframing, and interpersonal skills. In
addition to the neural changes deriving from cognitive
reframing and working through interpersonal challenges (as
described with CBT and IPT, resp.), mindfulness can be
associated with increased activity with more medial portions
of the PFC and ventral parts of the ACC [285], as well as
a decrease in amygdala activation [286]. Neural findings in
successful DBT have echoed these effects, showing increased
connectivity between vmPFC and amygdala (however, this
only occurred with active neurofeedback incorporated) [287]
and a decrease in amygdala activation [288].
Mentalization-based therapy has been shown to be help-
ful in both BPD and ASPD [289] and seeks to activate the
vmPFC by attempting to access the mind of the other and
assess the cognitive process which unfolds with this exercise.
To date, this author is unaware of neuroimaging studies which
assessed brain changes with this form of treatment, but it is an
exciting prospect for the future.
4.2.2. Other Psychotherapeutic Modalities. This section will
detail a number of different therapeutic modalities, with a
brief description of the treatment, the conditions for which it
Psychiatry Journal
is used, and the neurobiological effects seen with therapeutic
success. Table 2 describes the findings relating to these
different forms of therapy.
(1) Eye Movement Desensitization and Reprocessing (EMDR).
EMDR has been gaining significant ground in the PTSD lit-
erature [290]. It allows for recall of difficult/traumatic images
(at times with the aid of a script) while there is continued
sensory input. An MRI study utilizing EMDR described
the effects of 12 weeks of treatment [291]. In response to
treatment, there was a bilateral volumetric increase in the
hippocampus, showing enhanced ability to process traumatic
memories with greater contextual input and aiding with fear
extinction. The uncus (BA 36) is a portion of the parahip-
pocampal gyrus and has a role in repetition of stimuli that
have affective salience, as well as in the processing of defense
responses to perceived threat; successful EMDR has been
shown to decrease tracer uptake in this area, indicating
downregulation of heightened responsiveness [292].
(2) Prolonged Exposure (PE). PE, another treatment modality
employed in PTSD [203], consists of a combination of imag-
inal exposure (recounting the traumatic experience) and in
vivo exposure (confrontation of traumatic reminders which
had been avoided); this occurs as a manner of attempting to
allow cognitive restructuring and to extinguish conditioned
fear responses associated with triggers. Top-down control
of subcortical hyperactivity permits for fear extinction and
consolidation of more adaptive associations. Two studies
highlight an important contrast in terms of how this can take
place in response to PE. A study utilizing cognitive restruc-
turing with imaginal exposure utilized processing of fearful
faces to gauge treatment response [293]. Decrease in CAPS
scores correlated with an increase in rACC activity and a
decrease in bilateral amygdala activity, demonstrating the
greater inhibitory activation of this network during fear
processing. Another study employing a 10-week PE protocol
showed that fear extinction recall posttreatment was asso-
ciated with a decrease in rACC activation and increased
activity in the mPFC [294]. The rACC works in tandem
with the vmPFC and sgACC in regulating the fear response;
however, it has a function of monitoring external cues [295],
something which can be more or less adaptively activated
in individuals, depending on the surrounding structures’
connection to subcortical areas, and it would seem there is
not a straightforward correlation with symptom response in
PTSD, given the disparate findings regarding this area in the
two studies mentioned.
(3) Brief Eclectic Psychotherapy (BEP). BEP includes a number
of different technical elements, including imaginal exposure
and cognitive restructuring, in addition to some elements
of psychodynamic therapy and a farewell ritual when the
treatment is complete. BEP can be utilized for treating PTSD,
and there is a technical overlap with some elements of
PE, given the exposure and cognitive components of the
treatment. A study examining the effects of BEP on PTSD
patients assessed their ability to process traumatic material as
outlined in a script they prepared [253]. Successful treatment
21
correlated with a decrease in regional cerebral blood flow
(rCBF) in the right uncus (refer to the section on EMDR for
functional description of this structure); there seemed to be
conflicting finding regarding activation of the middle frontal
gyrus (MFG; both superior and middle FG are part of the
dlPFC). The authors highlighted how there are conflicting
findings in the literature regarding the MFG and how greater
or lower activation may depend on the script utilized.
(4) Interpersonal Therapy (IPT). IPT is a form of psy-
chotherapy which happens in a stepwise approach to aid the
individual in terms of understanding how to adapt to certain
life events which may be informing their depressed mood.
The main topics addressed include unresolved grief, role
conflict, role transitions, and interpersonal deficiencies [296].
The studies discussed in this section will refer to management
of MDD.
Retrieval of autobiographical memories may favor more
dorsal areas of the cingulate cortex, and this may be a factor
in the neural changes noted with IPT. There is increased
activity in the dACC and PCC noted in IPT responders
[145, 279], though subsequent activation of the dlPFC has
been inconsistently reported [146, 279]. The PCC is an area
involved in retrieval of episodic memory, and increased
activity may indicate an enhanced ability to access thought
and improve executive functioning [297]. As mentioned,
the PCC activation pattern differs from that described by
Kennedy et al. (2007) with CBT [273]; the reasons for this are
not entirely clear, though the function of this area with pain
perception (which may have a component of painful affect
retrieval), as well as more involved discussions in IPT relating
to active life role transitions with the component of grieving
(as opposed to the more cognitively based technique of CBT),
may have some relevance. Indeed, the PCC is involved in
remembering familiar individuals in one’s life as well as in the
neurobiology of grief and bereavement processes [298, 299].
4.2.3. Psychodynamic Psychotherapy. Psychodynamic psy-
chotherapy is essentially a form of insight-oriented treatment,
allowing patients to access origins of conflicts and understand
their sense of self, defensive structures (including efforts
to suppress emotional responses), and present interpersonal
functioning in light of early life experience. This is integrated
with an understanding of real-time dynamics with the thera-
pist, and an appreciation of transference-countertransference
factors can help illustrate the internalized relationship tem-
plates the patient may feel compelled to reenact. The latter
elements are conceptually important given the empathic
attunement element of the treatment (despite some level of
technical variation within schools of analytic thought), as this
may engage more ventral areas of the PFC and aid in decreas-
ing maladaptive dlPFC activity as well as amygdala hyperac-
tivity. In MDD, psychodynamic therapy promoted decreased
activation of the dorsally biased bottom-up network, with
mitigation of subcortical and limbic hyperactivity [300–303],
a decrease in sgACC hyperactivity (an area involved in poor
self-esteem, guilt, and repression of emotions) [300, 304],
diminished activity in dorsal areas of the mPFC (associ-
ated with ruminative self-referential thought) [300, 305],
22
increased activity in vPFC [302], and normalization of SERT
binding within medial portions of the PFC (as noted in
a SPECT study; PFC-amygdala top-down control relies on
serotonergic transporter integrity) [306, 307]. Modulation of
serotonergic transmission within the mPFC was shown in a
PET study assessing 5-HT1A density [308]. Psychodynamic
therapy was associated with greater binding of 5-HT1A in
the mPFC and OFC, a finding which correlated with clinical
improvement. As 5-HT1A is an inhibitory receptor, this may
serve to counterbalance excessive glutamatergic tone in a
number of brain regions; MDD has been associated with
greater 5-HT2 receptor density in the amygdala and PFC
[309], which has also been linked with suicidal behaviors.
Interestingly, the authors correlated the increase in 5-HT1A
binding with greater social functioning [310], replicating the
notion of heightened interpersonal attunement based on
experiencing an empathic other in a therapeutic setting.
Effects of psychodynamic therapy have also been studied
in subjects with BPD [311]. Pretreatment imaging showed
increased perfusion in limbic areas and diminished perfusion
in the PFC; throughout the course of treatment, there was
improvement in numerous clinical parameters (e.g., impul-
sivity, self-injurious behaviors, therapeutic alliance, and
adaptiveness of defense mechanisms), which correlated with
an increase in perfusion in the frontal cortex, reflecting
enhanced limbic modulation through cognitive strategies.
Table 3 outlines the studies regarding psychodynamic
psychotherapy. It should be noted that the open-endedness
of treatment lends itself to some replication challenges, and
there is a considerable difference in treatment length in some
of the studies mentioned.
4.3. Neural Predictors of Treatment Response to Psychotherapy.
Extending the understanding that has emerged from neural
changes which occur with successful courses of psychother-
apy, numerous studies have looked at activation patents
within neural areas or circuits which could potentially predict
an individual’s response to a particular therapeutic interven-
tion. Areas which are actively engaged during treatment may,
through established pretreatment activation patterns, lead
to further understanding of their role in psychopathology
and treatment response. Neuroimaging could therefore be an
ancillary method of tailoring treatment modalities to patients
suffering from particular conditions. The reader is referred to
additional reviews of the evolving use of this data in guiding
treatment [312–314]. Table 4 outlines the studies investigating
predictors of psychotherapeutic response.
As described in a previous section, individuals with
anxiety disorders can display heightened reactivity to threat.
Hyperactivity in particular brain areas involved with threat
appraisal and response has been shown to positively pre-
dict response to CBT in the treatment of anxiety. This
applies to activity patterns in the amygdala (both hyper- and
hypoactivity have been associated with predicting response)
[147, 262], as well as increased activity in the dACC, hip-
pocampus, and areas within the temporal and frontal lobes
involved with one’s reaction to threatening stimuli [147, 315–
317]. As these regions show changes over the course of
treatment, it is hypothesized that higher levels of activation
Psychiatry Journal
may indicate greater recruitment during interventions which
require modulatory network engagement. Functional cou-
pling between areas of the ACC and amygdala may predict
whether an individual will benefit from CBT. Activating the
dACC and a decreased dACC-amygdala coupling during
a self-criticism task has been shown to predict sustained
response to treatment one year later [318]. In addition,
increased pretreatment ACC-amygdala inhibitory coupling
during fear conditioning has been associated with treat-
ment response [148, 265]; interestingly, the l allele of the
5-HTTLPR polymorphism seems to be linked with this
greater coupling posttreatment and may drive treatment
response (though the allele per se does not seem to predict
response) [178]. Carriers of the s allele display a decrease
in the ACC-amygdala connectivity [319], which may be
responsible for considerable variation in temperamental
anxiety traits, and theoretically confer greater resistance
to therapeutic interventions. Another instance of genetic
susceptibility to treatment nonresponse pertains to the
5-HT1A rs6295 polymorphism; the G allele has been asso-
ciated with increased presynaptic autoreceptor expression
(decreasing serotonin release due to inhibitory feedback)
and decreased postsynaptic receptor expression (potentially
leading to heightened glutamatergic drive and contributing to
anxiety and depressive symptoms) [320]. The G/G genotype
has been associated with fear generalization, heightened
awareness to threatening stimuli, and greater avoidance and
escape behaviors, informed primarily by the amygdala and
hippocampus [149]. Resistance to CBT was shown in G/G
carriers, as indicated by continued amygdala hyperactivity in
response to threatening and safety cues, as well as inability
to promote differential conditioning in ACC and insulae;
G/G carriers also showed a decrease in self-initiated exposure
behaviors, decreasing likelihood of benefitting fully from
treatment [149].
In PTSD, pretreatment hyperactivity in amygdala and
ACC (both ventral and dorsal) was associated with treatment
nonresponse [282], which the authors hypothesized to indi-
cate excessive affective discharge given the rapid presentation
of stimuli, and question whether this is an adequate parallel
with PTSD, particularly given that this finding has been
challenged by other studies, which emphasize the importance
of engaging the ACC for adequate treatment response. Along
the same lines, a decrease in limbic and paralimbic gray
matter density was a predictor of treatment response in an
EMDR study [321]. As a corollary to the ability to appro-
priately control one’s responses to environmental stimuli,
PTSD subjects also showed greater response to CBT when
displaying higher pretreatment activation of frontostriatal
networks during inhibitory control tasks; in contrast, poor
response was predicted by pretreatment requirement of a
more widespread engagement of cortical and subcortical
areas to perform a similar task; thus, a more contained
preexisting circuitry can be strengthened by psychotherapy
[322].
With regard to the predictive neuroimaging findings for
the use of CBT for MDD, findings in the literature have at
times been contradictory, and further research efforts seem
warranted. Despite hyperactivity in the amygdala being
 Table 4: Description of psychotherapy and neuroimaging studies: predictors of therapeutic response.
Modality of
Diagnosis Study (including design if not previously outlined) Predictors of response
psychotherapy
Ball et al. (2014) Greater activation in hippocampus during maintenance of emotional response to
Psychiatry Journal

48 patients (25 GAD, 23 PD), all unmedicated negative images

CBT GAD fMRI Greater activation in anterior insula, superior temporal gyrus, supramarginal gyrus,
10 weekly sessions of CBT and superior frontal gyrus during cognitive reappraisal
McClure et al. (2007) Pretreatment amygdala hyperactivity
Greater pretreatment activation to angry versus neutral faces in portions of the
Doehrmann et al. (2013)
occipitotemporal cortices
Increased pretreatment activity to threat in the superior and middle temporal gyri
Klumpp et al. (2013)
and in the IFG. Hyperactivation to fearful faces in dmPFC, OFC, and dACC
Klumpp et al. (2014)
[147] Increased pretreatment activity (in the presence of emotional faces) in the dACC
fMRI and dmPFC
21 patients (unmedicated except for 2 on bupropion) Decreased pretreatment amygdala and mOFC activity during emotion processing
12 weekly 60-minute sessions
CBT SAD
Klumpp et al. (2014)
[148]
Greater pretreatment bilateral amygdala-pgACC connectivity
fMRI
21 patients (unmedicated except for 2 on bupropion)
12 weeks of CBT
Mansson et al. (2015)
Pretreatment dACC activation and lower dACC-amygdala coupling during
fMRI/support vector machines (SVM)
self-referential criticism task (92% balanced accuracy)∗ predicted sustained
26 patients (8 medicated)
response one year later
13 weeks of Internet-delivered CBT
Lueken et al. (2013) Greater pretreatment coupling between ACC and amygdala
Reinecke et al. (2014) Increased pretreatment activation in bilateral insulae and left dlPFC during threat
fMRI processing
CBT PD/AG 14 unmedicated patients with PD Increased right hippocampus gray matter
4 sessions of CBT
Straube et al. (2014) Nonresponse associated with heightened amygdala reactivity before and after
[149] treatment (informed by 5-HT1A rs6295 polymorphism G/G genotype)
Costafreda et al. (2009)
Response to treatment (gauged by response to sad faces) predicted by activity in the
16 unmedicated patients
ACC, superior and middle frontal cortices, paracentral cortex, superior parietal
fMRI
cortex, precuneus, and cerebellum
16 sessions of CBT
Crowther et al. (2015)
CBT MDD 20 unmedicated patients Pretreatment connectivity of the insula with the right medial temporal gyrus and
Resting-state functional connectivity MRI between the left intraparietal sulcus and OFC
Average of 12 sessions of BATD
Pretreatment activity in the dACC comparable to healthy controls predicted
Fu et al. (2008)
response
23
 24

Table 4: Continued.
Modality of
Diagnosis Study (including design if not previously outlined) Predictors of response
psychotherapy
Konarski et al. (2009)
7 unmedicated patients
Nonresponse associated with pretreatment hypermetabolism the interface of the
PET
pgACC and sgACC
16 sessions of CBT
Comparison group was on venlafaxine
Mackin et al. (2013)
Nonresponse associated with thinner bilateral PCC and parahippocampal cortex,
22 patients (not receiving antidepressants)
left paracentral, cuneus, and insular cortices, and right mOFC and lateral occipital
MRI
cortex
12 weeks of CBT
McGrath et al. (2014)
82 total patients (unmedicated prior to starting trial)
Nonresponse associated with pretreatment hyperactivity in the subcallosal cingulate
PET
and in the superior temporal sulcus
12–24 weeks of CBT and/or antidepressant
(escitalopram) treatment
Increased pretreatment vmPFC and dlPFC activity predicted response. Parameter
Ritchey et al. (2011)
analyzed was response to pictures of different affective valence
Siegle et al. (2006)
14 unmedicated patients Response to treatment was predicted by low sgACC reactivity and high amygdala
fMRI reactivity to negative words
16 sessions of CBT (12 weeks)
Pretreatment sgACC hyperactivity to positive (versus negative) stimuli predicted
Straub et al. (2015)
response
Thompson et al. (2015)
60 patients (59 years and older; 44 completed study;
Decrease in activation in left inferior frontal triangle and right superior frontal
83% on at least one medication, though type not
gyrus
specified)
Increase in activation of right middle frontal gyrus and left superior frontal gyrus
fMRI
12 weeks of CBT
Walsh et al. (2016)
During anticipation phase, response was associated with: greater caudate-dACC
33 unmedicated patients
and caudate-rACC connectivity; greater right putamen-right OFC connectivity;
fMRI
decreased connectivity between right mPFC and dACC; and decreased connectivity
Up to 15 BATD sessions (average of 11.67 weekly
between left putamen and the subcallosal cortex
sessions)
Pretreatment decreased activity in vACC during self-referential information
Yoshimura et al. (2014)
processing
Pretreatment hyperactivity in amygdala, vACC, and dACC was associated with
Bryant et al. (2008)
nonresponse
Falconer et al. (2013)
CBT PTSD 13 patients Treatment response was predicted by higher pretreatment activation of
(6 on stable doses of SSRIs) frontostriatal networks (vlPFC, OFC, mPFC, and dorsal striatum) during inhibitory
fMRI control tasks (this study employed Go/No-Go task)
8 weeks of CBT
Psychiatry Journal
 Psychiatry Journal

Table 4: Continued.
Modality of
Diagnosis Study (including design if not previously outlined) Predictors of response
psychotherapy
Buchheim et al. (2012) Increased pretreatment activity in the sgACC may predict response
Psychodynamic
MDD Pretreatment right precuneus metabolism (significantly higher in treatment
psychotherapy Roffman et al. (2014) completers; correlated also with psychological mindedness)
Guided imagery MDD Huang et al. (2014) Increased pretreatment regional homogeneity within the dACC
Nardo et al. (2010)
20 patients (15 completed EMDR); unclear if patients
were medicated or not (it was not an exclusion
EMDR PTSD Decreased gray matter density in limbic and paralimbic cortices
criterion)
MRI
Five 90-minute sessions
∗
Balanced accuracy is a mean of sensitivity and specificity.
25
26
described in MDD, this has not been a consistent region of
interest (ROI) in studies assessing neurobiological change
with treatment. Network remodulation on a “cortico-
cortical” level may be more salient in assessing the effects
of CBT for depressed patients [323], given the rumina-
tive and negative thought patterns that emerge (different
from anxiety and trauma-related disorders, in which the
immediately threatening component is of prime concern
and in need of attention and active cognitive reworking
to promote symptom improvement). Though subsequent
top-down influence will be paramount in modifying insula
and amygdala-based negative salience of environment and
self, predictive factors regarding treatment outcome seem
to lie more within PFC and ACC patterns of activation
[324], and dysfunctional PFC-ACC can be responsive to CBT
[325]. Amygdala hyperactivity is mitigated with treatment,
but it is not a consistent predictor of response to CBT in
subjects with MDD. Greater pretreatment activation of both
dL and vmPFC areas is predictor of successful treatment
outcomes [241, 326]. Activity in these areas would allow for
individuals to, respectively, engage in cognitive reappraisal
(a function which can be impaired in MDD) [326] as well
as allowing for more active vmPFC-amygdala control over
the course of treatment, limiting subcortical input which
could make the work overwhelming or distressing, hindering
progress. There are conflicting findings in the literature with
regard to predictive factors relating to activity within the
different areas of the ACC, as functional divisions are not
entirely clear. Within the subdivisions of the ventral portions
of the ACC, the “affective” and “cognitive” functions may
at times be less clear-cut, and it has been hypothesized
that the pregenual cingulate is something of a watershed
area [327]. This overlap can be appreciated with regard to
the dlPFC and its connectivity to both rACC [Brodmann
area (BA) 24] and sgACC (BA 25). Treatment nonresponse
has been associated with a decrease in dlPFC metabolism
and decreased activity in the rACC [273, 328]; this may
reflect difficulty accessing executive functioning regions of
the brain as well as top-down regulatory areas, making it
difficult to engage in the process inherent to CBT, particularly
working with distorted cognitive patterns. In MDD patients,
the sgACC has been shown to have decreased gray matter
volume and metabolic activity [329]. Low baseline sgACC
activity and deficient sgACC-amygdala regulatory coupling
may inform negatively ruminative thought patterns [330],
and it has been hypothesized that CBT will be most useful in
these cases because the inhibitory control can be enhanced
through successful therapy [330]. Hyperactivity in a region
between the rACC and sgACC has been associated with
resistance to both CBT and antidepressant response [331,
332]. In effect, response to CBT seems to be favored in
patients with a stronger rACC-dlPFC and a weaker sgACC-
amygdala pretreatment activity, suggesting that revisiting
maladaptive schema indeed requires active revisiting of one’s
cognitive distortions, and enhanced top-down control may
be more important with regard to the vmPFC. However, it
is not entirely clear whether circumscribed functions and
responses of the sgACC can be promoted, in particular as
Psychiatry Journal
this area can undergo, as mentioned, different activation pat-
terns posttreatment [273, 280, 332]. Interestingly, increased
activity in the sgACC may predict response to psychody-
namic therapy in depressed patients (activity which lessened
over the course of treatment) [300]. Interpretation of this
finding is somewhat conjectural, though given the variable
nature of technique in psychodynamic therapy, preemptively
active engagement of sgACC-limbic networks may be more
adaptive depending on the material that is revisited. In
a study utilizing the Core Conflictual Relationship Theme
(CCRT) manual to guide psychodynamic psychotherapy,
treatment was associated with a decrease in insula activation
[303]; in addition, precuneus activity prior to therapy was
associated with greater psychological mindedness (associated
with modest predictive value in dynamic therapy) [333]; both
areas are associated with self-attributional beliefs; thus, being
able to realistically access one’s understanding of internal
responsibility for external events (balanced between anterior
and posterior portions of the precuneus) may help [334], par-
ticularly in this model of therapy, which reworks problematic
interpersonal relationships. Importantly for psychodynamic
therapy, the precuneus is involved in several dimensions of
self-awareness, including taking the first-person perspective,
episodic memory, and self-agency [335]. In addition to its
implications in dynamic therapy, thinning of the precuneus
can predict nonresponse to CBT in late-life depression [336].
The dACC has also been implicated in predicting
response to CBT. Fu et al. (2008) showed that pretreatment
activity within the dACC which was comparable to healthy
controls predicted a successful therapeutic response [240],
which the authors correlated with involvement of the area in
tasks associated with potential loss of reward; thus, normal
activity in the midst of a major depressive episode may be an
indicator of resilience. While the dACC may be implicated
in ruminative and excessive cognitive control, increased
dACC-dlPFC connectivity (akin to increased rACC-dlPFC
coupling) may be adaptive in the task of engaging in actively
reworking modes of thinking in CBT, allowing for greater
treatment benefits. Areas of the cingulate and PFC are also
implicated in reward processing (which may serve as models
for anhedonia), in particular relating to their connectivity
with striatal regions. Two studies utilized behavioral acti-
vation treatment for depression (BATD), which is geared
specifically towards having patients interact in a sustained
manner with positively reinforcing stimuli, attempting to
ameliorate reward processing dysfunction [337, 338]. In one,
response to treatment was predicted by greater connectivity
between the caudate-dACC and caudate-rACC, as well as
by greater connectivity between right putamen and right
OFC (refer to Table 4 for additional findings). Within the
reward paradigm, the dACC is associated with estimating
potential values of rewards and cognitively gauging whether
to consider a determined action [337]. Thus, as alluded to
earlier, selective hyperactivity within the dACC may facilitate
cognitive reworking in MDD while maintaining active ability
to process reward, predicting better outcomes. In addition to
connectivity with basal ganglia, enhanced connectivity of the
OFC (involved with assigning salience to stimuli, as well as
Psychiatry Journal
with reward processing and feedback) with cortical regions
was also shown to be a predictor of treatment [338].
This brief discussion highlights that certain preexisting
network activation, while contributing to some dimensions
of psychopathology, may also be adaptive in allowing for
optimal engagement in therapy and maximizing the response
to treatment.
4.4. Interpersonal Component as Modifier of Neural Circuitry.
Though intuitive, one aspect of psychotherapy is the funda-
mentally dyadic nature of this treatment modality. In keeping
with the argument put forth by this paper, early life adversity
and lack of dyadic attunement can create a neural circuitry
which effectively diverts one from accessing the intensity of
the affective response and turns to more cognitive control
mechanisms as a default form of coping, in effect evading a
more integrated manner of thinking. This template can lead
to subsequent psychopathology and more ingrained view
of self and others, ruminating on themes of worthlessness,
isolation, and mistrust with regard to the intention of others.
Reactivity within subcortical areas tends to magnify these
core beliefs, requiring modulation by higher cortical areas
which may not be capable of effecting such change. Through
the dyadic interaction of the psychotherapy setting, a new
pattern of interpersonal relating can be fostered, one based on
empathic attunement and allowing for exploration of highly
sensitive themes in a safe setting. The establishment of this
relationship can allow for a restructuring of these default
modes of responding, creating greater fluidity between dif-
ferent PFC areas, in particular accessing areas involved with
empathic responses (i.e., vmPFC), which also are instrumen-
tal in controlling subcortical areas which impose a bottom-
up, affectively driven response to stimuli. Interestingly, one
of the trending modalities for treatment of PTSD is the
adjunct use of methylenedioxymethamphetamine (MDMA)
in addition to psychotherapy; one of the principles behind
such an addition is to facilitate the “empathogenic” abilities
of the patient, allowing for greater interpersonal comfort and
thus “open up” about traumatic experiences without over-
whelming anxiety or vigilance about the therapist [339, 340].
A good degree of controversy surrounds generalizing this
viewpoint across psychotherapeutic modalities, as discussed.
One of the more consistent forms of therapy in which this
medialization is appreciated is psychodynamically oriented
psychotherapy. The focus on the interpersonal relationship
in the room, honing in on transference dynamics may
contribute to the more consistent findings of medial structure
activation, given the “real-time” interpersonal component
which is intrinsic to the technical approach.
As an interesting contrast, meditation practitioners (who
engage in an inherently solo practice) show a deactivation
of the amygdala through increased activity in the dlPFC and
decreased activity in the mPFC, indicating that heightening
attention, self-monitoring, and executive/cognitive control
can decrease one’s visceral response, in a manner disengaged
from the interpersonal circuitry discussed before [341, 342].
A similar phenomenon has been observed in practitioners of
mindfulness, which borrows some of the same principles of
meditation [343].
27
5. Conclusions
This paper focused on multiple aspects of environmental
input on epigenetic and neural circuitry components. It
highlighted how early life adversity can lead to repression
of key genes through methylation processes and to the
template of concretized forms of thinking which can be
internalized as default modes of negotiating the environment.
The reparative effects of the latter will be contingent on
the presence of a nurturing other who can allow for the
patient to feel a level of attunement which may have been
lacking earlier in life. The purported lack of containment
by the primary caregiver as a child can have long-lasting
effects on genetic, neuroendocrine, and circuitry levels and
inform multiple arenas of psychopathology. However, there
is notable plasticity within areas of the CNS, facilitated by
gene malleability promoted by demethylation, something
which can be observed with positive environmental input
(e.g., exercise, positive social environments, and psychother-
apy), bolstered by the plastic effects of psychopharmacologic
agents (indeed, the epigenetic effects of medications are well
recognized as a potential ancillary component to enhance
psychotherapy) [344]. As imaging and genetic research grows
in sophistication, predictors of treatment response (both
pertaining to medications and psychotherapy) may allow for
more tailored approaches to patient care [314, 345]. There are
still some conflicting findings in the literature which have
made some extrapolations somewhat tenuous, as resting-
state functional imaging can differ from more dynamic task
assessments; also, the expression of certain genes which
control circulating stress hormones and those promoting
neuroplasticity do not always show straightforward corre-
lations with symptom response. This in part stems from
inconsistent findings regarding the influence of cortisol on
memory consolidation, as well as the complicated relation-
ship between neurotransmitters and psychopathology (e.g.,
the relationship between BDNF and the serotonergic system),
something which is strongly underlined by the concept of
differential susceptibility. The continued input of the envi-
ronment is paramount in determining how risk or resilience
factors will translate as such, inviting our field to revisit such
dichotomous concepts and appreciate the dynamic and ever-
evolving nature of gene-environment interactions. A truism
has become the importance of therapeutic rapport, and
the progressive medialization of neural circuitry observed
with numerous forms of psychotherapy found by researchers
assessing responses in a number of psychiatric conditions
illustrates that the empathic interpersonal element is a vital
component to treatment which transcends technique, allow-
ing for the safety and novelty of a containing setting to
provide the patient with means to reach into the depths of
their conflicts and not feel alone.
Conflicts of Interest
The author declares that there are no conflicts of interest
regarding the publication of this paper.
28
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